Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy

ABSTRACT

The present invention relates to aminotetraline derivatives of the formula (I) 
                         
or a physiologically tolerated salt thereof.
 
     The invention relates to pharmaceutical compositions comprising such aminotetraline derivatives, and the use of such aminotetraline derivatives for therapeutic purposes. The aminotetraline derivatives are GlyT1 inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. patent application Ser. No.12/706,326, filed on Feb. 16, 2010, now U.S. Pat. No. 8,563,617, whichclaims priority to U.S. Provisional Patent Application No. 61/152,825,filed on Feb. 16, 2009, the contents of all of which are herein fullyincorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to aminotetraline derivatives,pharmaceutical compositions comprising such aminotetraline derivatives,and the use of such aminotetraline derivatives for therapeutic purposes.The aminotetraline derivatives are GlyT1 inhibitors.

Dysfunction of glutamatergic pathways has been implicated in a number ofdisease states in the human central nervous system (CNS) including butnot limited to schizophrenia, cognitive deficits, dementia, Parkinsondisease, Alzheimer disease and bipolar disorder. A large number ofstudies in animal models lend support to the NMDA hypofunctionhypothesis of schizophrenia.

NMDA receptor function can be modulated by altering the availability ofthe co-agonist glycine. This approach has the critical advantage ofmaintaining activity-dependent activation of the NMDA receptor becausean increase in the synaptic concentration of glycine will not produce anactivation of NMDA receptors in the absence of glutamate. Since synapticglutamate levels are tightly maintained by high affinity transportmechanisms, an increased activation of the glycine site will onlyenhance the NMDA component of activated synapses.

Two specific glycine transporters, GlyT1 and GlyT2 have been identifiedand shown to belong to the Na/Cl-dependent family of neurotransmittertransporters which includes taurine, gamma-aminobutyric acid (GABA),proline, monoamines and orphan transporters. GlyT1 and GlyT2 have beenisolated from different species and shown to have only 50% identity atthe amino acid level. They also have a different pattern of expressionin mammalian central nervous system, with GlyT2 being expressed inspinal cord, brainstem and cerebellum and GlyT1 present in these regionsas well as forebrain areas such as cortex, hippocampus, septum andthalamus. At the cellular level, GlyT2 has been reported to be expressedby glycinergic nerve endings in rat spinal cord whereas GlyT1 appears tobe preferentially expressed by glial cells. These expression studieshave led to the suggestion that GlyT2 is predominantly responsible forglycine uptake at glycinergic synapses whereas GlyT1 is involved inmonitoring glycine concentration in the vicinity of NMDA receptorexpressing synapses. Recent functional studies in rat have shown thatblockade of GlyT1 with the potent inhibitor(N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl])-sarcosine (NFPS)potentiates NMDA receptor activity and NMDA receptor-dependent long-termpotentiation in rat.

Molecular cloning has further revealed the existence of three variantsof GlyT1, termed GlyT-1a, GlyT-1b and GlyT-1c, each of which displays aunique distribution in the brain and peripheral tissues. The variantsarise by differential splicing and exon usage, and differ in theirN-terminal regions.

The physiological effects of GlyT1 in forebrain regions together withclinical reports showing the beneficial effects of GlyT1 inhibitorsarcosine in improving symptoms in schizophrenia patients suggest thatselective GlyT1 inhibitors represent a new class of antipsychotic drugs.

Glycine transporter inhibitors are already known in the art, forexample:

(see also Hashimoto K., Recent Patents on CNS Drug Discovery, 2006, 1,43-53; Harsing L. G. et al., Current Medicinal Chemistry, 2006, 13,1017-1044; Javitt D. C., Molecular Psychiatry (2004) 9, 984-997;Lindsley, C. W. et al., Current Topics in Medicinal Chemistry, 2006, 6,771-785; Lindsley C. W. et al., Current Topics in Medicinal Chemistry,2006, 6, 1883-1896).

It was one object of the present invention to provide further glycinetransporter inhibitors.

SUMMARY OF THE INVENTION

The present invention relates to aminotetraline derivatives of theformula (I)

-   -   wherein

-   A is a 5- or 6-membered ring;

-   R is R¹—W-A¹-Q-Y-A²-X¹—;

-   R¹ is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl,    trialkylsilylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,    alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylaminoalkyl,    alkyloxycarbonylaminoalkyl, alkylaminocarbonylaminoalkyl,    dialkylaminocarbonyl-aminoalkyl, alkylsulfonylaminoalkyl,    (optionally substituted arylalkyl), aminoalkyl, optionally    substituted arylalkyl, optionally substituted heterocyclylalkyl,    cycloalkyl, alkylcarbonyl, alkoxycarbonyl, halogenated    alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,    (halogenated alkyl)aminocarbonyl, arylaminocarbonyl, alkenyl,    alkynyl, optionally substituted aryl, hydroxy, alkoxy, halogenated    alkoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy,    dialkylaminoalkoxy, alkylcarbonylaminoalkoxy,    arylcarbonylaminoalkoxy, alkoxycarbonylaminoalkoxy, arylalkoxy,    alkylsulfonylaminoalkoxy, (halogenated alkyl)sulfonylaminoalkoxy,    arylsulfonylaminoalkoxy, (arylalkyl)sulfonylaminoalkoxy,    heterocyclylsulfonylaminoalkoxy, heterocyclylalkoxy, aryloxy,    heterocyclyloxy, alkylthio, halogenated alkylthio, alkylamino,    (halogenated alkyl)amino, dialkylamino, di(halogenated alkyl)amino,    alkylcarbonylamino, (halogenated alkyl)carbonylamino,    arylcarbonylamino, alkylsulfonylamino, (halogenated    alkyl)sulfonylamino, arylsulfonylamino or optionally substituted    heterocyclyl;

-   W is —NR⁸— or a bond;

-   A¹ is optionally substituted alkylene or a bond;

-   Q is —S(O)₂— or —C(O)—;

-   Y is —NR⁹— or a bond;

-   A² is optionally substituted alkylene, alkylene-CO—, —CO-alkylene,    alkylene-O-alkylene, alkylene-NR¹⁸-alkylene, optionally substituted    alkenylen, optionally substituted alkynylene, optionally substituted    arylene, optionally substituted heteroarylene or a bond;

-   X¹ is —O—, —NR¹¹—, —S—, optionally substituted alkylene, optionally    substituted alkenylen, optionally substituted alkynylene;

-   R² is hydrogen, halogen, alkyl, halogenated alkyl, hydroxyalkyl,    —CN, alkenyl, alkynyl, optionally substituted aryl, hydroxy, alkoxy,    halogenated alkoxy, alkoxycarbonyl, alkenyloxy, arylalkoxy,    alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl,    aminosulfonyl, amino, alkylamino, alkenylamino, nitro or optionally    substituted heterocyclyl, or two radicals R² together with the ring    atoms of A to which they are bound form a 5- or 6-membered ring;

-   R³ is hydrogen, halogen, alkyl or alkoxy, or two radicals R³    together with the carbon atom to which they are attached form a    carbonyl group;

-   R^(4a) is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, CH₂CN, —CHO, alkylcarbonyl,    (halogenated alkyl)carbonyl, arylcarbonyl, alkoxycarbonyl,    aryloxycarbonyl, alkylaminocarbonyl, alkenyl, —C(═NH)NH₂,    —C(═NH)NHCN, alkylsulfonyl, arylsulfonyl, amino, —NO or    heterocyclyl;

-   R^(4b) is hydrogen, alkyl, halogenated alkyl, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, CH₂CN, —CHO, alkylcarbonyl, (halogenated    alkyl)carbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,    alkylaminocarbonyl, alkenyl, —C(═NH)NH₂, —C(═NH)NHCN, alkylsulfonyl,    arylsulfonyl, amino, —NO or heterocyclyl; or

-   R^(4a), R^(4b) together are optionally substituted alkylene, wherein    one —CH₂— of alkylene may be replaced by an oxygen atom or —NR¹⁶;

-   X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond;

-   X³ is —O—, —NR⁷—, —S—, >CR^(13a)R^(13b) or a bond;

-   R⁵ is optionally substituted aryl, optionally substituted cycloalkyl    or optionally substituted heterocyclyl;

-   n is 0, 1 or 2;

-   R⁶ is hydrogen or alkyl;

-   R⁷ is hydrogen or alkyl;

-   R⁹ is hydrogen or alkyl;

-   R⁹ is hydrogen, alkyl, cycloalkyl, aminoalkyl, optionally    substituted arylalkyl or heterocyclyl; or

-   R⁹, R¹ together are alkylene; or

-   R⁹ is alkylene that is bound to a carbon atom in A² and A² is    alkylene or to a carbon atom in X¹ and X¹ is alkylene;

-   R¹⁰ is hydrogen, alkyl or alkylsulfonyl;

-   R¹¹ is hydrogen or alkyl, or

-   R⁹, R¹¹ together are alkylene,

-   R^(12a) is hydrogen, optionally substituted alkyl, alkylaminoalkyl,    dialkylaminoalkyl, heterocyclylalkyl, optionally substituted aryl or    hydroxy;

-   R^(12b) is hydrogen or alkyl, or

-   R¹²a, R^(12b) together are carbonyl or optionally substituted    alkylene, wherein one —CH₂— of alkylene may be replaced by an oxygen    atom or —NR¹⁴—;

-   R^(13a) is hydrogen, optionally substituted alkyl, alkylaminoalkyl,    dialkylaminoalkyl, heterocyclylalkyl, optionally substituted aryl or    hydroxy;

-   R^(13b) is hydrogen or alkyl, or

-   R^(13a), R^(13b) together are carbonyl or optionally substituted    alkylene, wherein one —CH₂— of alkylene may be replaced by an oxygen    atom or —NR¹⁵—;

-   R¹⁴ is hydrogen or alkyl;

-   R¹⁵ is hydrogen or alkyl; and

-   R¹⁶ is hydrogen or alkyl,    or a physiologically tolerated salt thereof.

Thus, the present invention relates to aminotetraline derivatives havingthe formula (Ia)

wherein A, R¹, W, A¹, Q, Y, A², X¹, R², R³, R^(4a), R^(4b), X², X³, R⁵,n are as defined herein.

Further, the present invention relates to aminotetraline derivatives offormula (I) wherein R is —CN, i.e. aminotetraline derivatives having theformula (Ib)

wherein A, R², R³, R^(4a), R^(4b), X², X³, R⁵, n are as defined herein.

Thus, the term aminotetraline derivative is used herein to denote inparticular aminotetralines (n=1) and fused cyclohexanes (n=1) whereinthe benzene ring is replaced by a 5- or 6-membered heterocyclic ring aswell as homologous bicyclic compounds wherein n is 0 or 2.

Said compounds of formula (I), i.e., the aminotetraline derivatives offormula (I) and their physiologically tolerated acid addition salts, areglycine transporter inhibitors and thus useful as pharmaceuticals.

The present invention thus further relates to the compounds of formula(I) for use in therapy.

The present invention also relates to pharmaceutical compositions whichcomprise a carrier and a compound of formula (I).

In particular, said compounds, i.e., the aminotetraline derivatives andtheir physiologically tolerated acid addition salts, are inhibitors ofthe glycine transporter GlyT1.

The present invention thus further relates to the compounds of formula(I) for use in inhibiting the glycine transporter.

The present invention also relates to the use of the compounds offormula (I) in the manufacture of a medicament for inhibiting theglycine transporter GlyT1 and corresponding methods of inhibiting theglycine transporter GlyT1.

Glycine transport inhibitors and in particular inhibitors of the glycinetransporter GlyT1 are known to be useful in treating a variety ofneurologic and psychiatric disorders.

The present invention thus further relates to the compounds of formula(I) for use in treating a neurologic or psychiatric disorder.

The present invention further relates to the compounds of formula (I)for use in treating pain.

The present invention also relates to the use of the compounds offormula (I) in the manufacture of a medicament for treating a neurologicor psychiatric disorder and corresponding methods of treating saiddisorders. The present invention also relates to the use of thecompounds of formula (I) in the manufacture of a medicament for treatingpain and corresponding methods of treating pain.

The present invention further relates to aminotetraline derivatives offormula (II)

wherein L is an amino-protecting group, Y is NR⁹, and A², X¹, R², R³,R^(4a), R^(4b), X², X³, R⁵, n and R⁹ are defined as above.

The aminotetraline derivatives of formula (II) are useful asintermediates in the preparation of GlyT1 inhibitors, in particularthose of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Provided that the aminotetraline derivatives of the formula (I) or (II)of a given constitution may exist in different spatial arrangements, forexample if they possess one or more centers of asymmetry,polysubstituted rings or double bonds, or as different tautomers, it isalso possible to use enantiomeric mixtures, in particular racemates,diastereomeric mixtures and tautomeric mixtures, preferably, however,the respective essentially pure enantiomers, diastereomers and tautomersof the compounds of formula (I) or (II) and/or of their salts.

According to one embodiment, an enantiomer of the aminotetralinederivatives of the present invention has the following formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³, R⁵, n are as definedherein.

According to another embodiment, an enantiomer of the aminotetralinederivatives of the present invention has the following formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³, R⁵, n are as definedherein.

According to one embodiment, an enantiomer of the aminotetralinederivatives of the present invention has the following formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³, R⁵, n are as definedherein.

According to another embodiment, an enantiomer of the aminotetralinederivatives of the present invention has the following formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³, R⁵, n are as definedherein.

The physiologically tolerated salts of the aminotetraline derivatives ofthe formula (I) or (II) are especially acid addition salts withphysiologically tolerated acids. Examples of suitable physiologicallytolerated organic and inorganic acids are hydrochloric acid, hydrobromicacid, phosphoric acid, sulfuric acid, C₁-C₄-alkylsulfonic acids, such asmethanesulfonic acid, cycloaliphatic sulfonic acids, such asS-(+)-10-campher sulfonic acid, aromatic sulfonic acids, such asbenzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylicacids and hydroxycarboxylic acids having 2 to 10 carbon atoms, such asoxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid,tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid.Other utilizable acids are described, e.g., in Fortschritte derArzneimittelforschung [Advances in drug research], Volume 10, pages 224ff., Birkhäuser Verlag, Basel and Stuttgart, 1966.

The present invention moreover relates to compounds of formula (I) or(II) as defined herein, wherein at least one of the atoms has beenreplaced by its stable, non-radioactive isotope (e.g., hydrogen bydeuterium, ¹²C by ¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein atleast one hydrogen atom has been replaced by a deuterium atom.

Of course, such compounds contain more of the respective isotope thanthis naturally occurs and thus is anyway present in the compounds (I) or(II).

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactiveisotopes which contain one or more additional neutron than the normallyabundant isotope of the respective atom. Deuterated compounds have beenused in pharmaceutical research to investigate the in vivo metabolicfate of the compounds by evaluation of the mechanism of action andmetabolic pathway of the non deuterated parent compound (Blake et al. J.Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are importantin the design of safe, effective therapeutic drugs, either because thein vivo active compound administered to the patient or because themetabolites produced from the parent compound prove to be toxic orcarcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp.Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J.Physiol. Pharmacol., 77, 79-88 (1999).

Incorporation of a heavy atom particularly substitution of deuterium forhydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug. This effect is usually insignificant ifthe label is placed at a metabolically inert position of the molecule.

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These changes may influencethe fate of the drug at different steps along its passage through thebody. Absorption, distribution, metabolism or excretion can be changed.Absorption and distribution are processes that depend primarily on themolecular size and the lipophilicity of the substance. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breakingof a chemical bond to a deuterium atom is the rate limiting step in theprocess. While some of the physical properties of a stableisotope-labeled molecule are different from those of the unlabeled one,the chemical and biological properties are the same, with one importantexception: because of the increased mass of the heavy isotope, any bondinvolving the heavy isotope and another atom will be stronger than thesame bond between the light isotope and that atom. In any reaction inwhich the breaking of this bond is the rate limiting step, the reactionwill proceed slower for the molecule with the heavy isotope due to“kinetic isotope effect”. A reaction involving breaking a C-D bond canbe up to 700 percent slower than a similar reaction involving breaking aC—H bond. If the C-D bond is not involved in any of the steps leading tothe metabolite, there may not be any effect to alter the behavior of thedrug. If a deuterium is placed at a site involved in the metabolism of adrug, an isotope effect will be observed only if breaking of the C-Dbond is the rate limiting step. There is evidence to suggest thatwhenever cleavage of an aliphatic C—H bond occurs, usually by oxidationcatalyzed by a mixed-function oxidase, replacement of the hydrogen bydeuterium will lead to observable isotope effect. It is also importantto understand that the incorporation of deuterium at the site ofmetabolism slows its rate to the point where another metabolite producedby attack at a carbon atom not substituted by deuterium becomes themajor pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in somecases repeatedly, of thousands of milligrams of deuterated water, arealso used in healthy humans of all ages, including neonates and pregnantwomen, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control.Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al.Am. J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that anydeuterium released, for instance, during the metabolism of compounds ofthis invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) andnatural abundance of deuterium (approximately 0.015%) indicates that a70 kg human normally contains nearly a gram of deuterium. Furthermore,replacement of up to about 15% of normal hydrogen with deuterium hasbeen effected and maintained for a period of days to weeks in mammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.Physiol. 1961 201: 357). Higher deuterium concentrations, usually inexcess of 20%, can be toxic in animals. However, acute replacement of ashigh as 15%-23% of the hydrogen in humans' fluids with deuterium wasfound not to cause toxicity (Blagojevic N et al. in “Dosimetry &Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares Gand Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above itsnatural abundance is called enrichment or deuterium-enrichment. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have differentcapacities for exchange with deuterium. Certain hydrogen atoms areeasily exchangeable under physiological conditions and, if replaced bydeuterium atoms, it is expected that they will readily exchange forprotons after administration to a patient. Certain hydrogen atoms may beexchanged for deuterium atoms by the action of a deuteric acid such asD₂SO₄/D₂O. Alternatively, deuterium atoms may be incorporated in variouscombinations during the synthesis of compounds of the invention. Certainhydrogen atoms are not easily exchangeable for deuterium atoms. However,deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates during theconstruction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can beprepared by using known methods described in the literature. Suchmethods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Relevant procedures and intermediates are disclosed,for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B etal., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223,WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and USPatent Application Publication Nos. 20090137457; 20090131485;20090131363; 20090118238; 20090111840; 20090105338; 20090105307;20090105147; 20090093422; 20090088416; 20090082471, the methods arehereby incorporated by reference.

The organic moieties mentioned in the above definitions of the variablesare—like the term halogen—collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

Unless indicated otherwise, the term “substituted” means that a radicalis substituted with 1, 2 or 3, especially 1, substituent which are inparticular selected from the group consisting of halogen, C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, C₃-C₁₂-heterocyclyl-alkyl, C₁-C₄-alkoxyC₁-C₄-alkyl,amino-C₁-C₄-alkyl, C₁-C₄-alkenyl, OH, SH, CN, CF₃, O—CF₃, COOH,O—CH₂—COOH, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₃-C₇-cycloalkyl,COO—C₁-C₆-alkyl, CONH₂, CONH—C₁-C₆-alkyl, SO₂NH—C₁-C₆-alkyl,CON—(C₁-C₆-alkyl)₂, SO₂N—(C₁-C₆-alkyl)₂, NH₂, NH—C₁-C₆-alkyl,N—(C₁-C₆-alkyl)₂, NH—(C₁-C₄-alkyl-C₆-C₁₂-aryl), NH—CO—C₁-C₆-alkyl,NH—SO₂—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl, C₆-C₁₂-aryl, O—C₆-C₁₂-aryl,O—CH₂—C₆-C₁₂-aryl, CONH—C₆-C₁₂-aryl, SO₂NH—C₆-C₁₂-aryl,CONH—C₃-C₁₂-heterocyclyl, SO₂NH—C₃-C₁₂-heterocyclyl, SO₂—C₆-C₁₂-aryl,NH—SO₂—C₆-C₁₂-aryl, NH—CO—C₆-C₁₂-aryl, NH—SO₂—C₃-C₁₂-heterocyclyl,NH—CO—C₃-C₁₂-heterocyclyl and C₃-C₁₂-heterocyclyl, wherein aryl andheterocyclyl in turn may be unsubstituted or substituted with 1, 2 or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄ haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

The term halogen denotes in each case fluorine, bromine, chlorine oriodine, in particular fluorine or chlorine.

C₁-C₄-Alkyl is a straight-chain or branched alkyl group having from 1 to4 carbon atoms. Examples of an alkyl group are methyl, C₂-C₄-alkyl suchas ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl ortert-butyl. C₁-C₂-Alkyl is methyl or ethyl, C₁-C₃-alkyl is additionallyn-propyl or isopropyl.

C₁-C₆-Alkyl is a straight-chain or branched alkyl group having from 1 to6 carbon atoms. Examples include methyl, C₂-C₄-alkyl as mentioned hereinand also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

C₁-C₄-Alkyl and C₁-C₆-Alkyl are further meant to denote alkyl radicalswhich are substituted with 1, 2 or 3 substituents which areindependently selected from the substituents listed under the abovedefinition of the term “substituted”. Examples of substituted alkylradicals are listed in the following.

Halogenated C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 orall of the hydrogen atoms are replaced by 1, 2, 3, 4 or a correspondingnumber of identical or different halogen atoms, such as inhalogenomethyl, dihalogenomethyl, trihalogenomethyl,(R)-1-halogenoethyl, (S)-1-halogenoethyl, 2-halogenoethyl,1,1-dihalogenoethyl, 2,2-dihalogenoethyl, 2,2,2-trihalogenoethyl,(R)-1-halogenopropyl, (S)-1-halogenopropyl, 2-halogenopropyl,3-halogenopropyl, 1,1-dihalogenopropyl, 2,2-dihalogenopropyl,3,3-dihalogenopropyl, 3,3,3-trihalogenopropyl,(R)-2-halogeno-1-methylethyl, (S)-2-halogeno-1-methylethyl,(R)-2,2-dihalogeno-1-methylethyl, (S)-2,2-dihalogeno-1-methylethyl,(R)-1,2-dihalogeno-1-methylethyl, (S)-1,2-dihalogeno-1-methylethyl,(R)-2,2,2-trihalogeno-1-methylethyl,(S)-2,2,2-trihalogeno-1-methylethyl, 2-halogeno-1-(halogenomethyl)ethyl,1-(dihalogenomethyl)-2,2-dihalogenoethyl, (R)-1-halogenobutyl,(S)-1-halogenobutyl, 2-halogenobutyl, 3-halogenobutyl, 4-halogenobutyl,1,1-dihalogenobutyl, 2,2-dihalogenobutyl, 3,3-dihalogenobutyl,4,4-dihalogenobutyl, 4,4,4-trihalogenobutyl, etc. Particular examplesinclude the fluorinated C₁-C₄ alkyl groups as defined, such astrifluoromethyl.

C₆-C₁₂-Aryl-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by C₆-C₁₂-aryl, such as in benzyl.

Hydroxy-C₁-C₄-alkyl is a straight-chain or branched alkyl group having 1to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or2 carbon atoms, wherein one or two hydrogen atoms are replaced by one ortwo hydroxyl groups, such as in hydroxymethyl, (R)-1-hydroxyethyl,(S)-1-hydroxyethyl, 2-hydroxyethyl, (R)-1-hydroxypropyl,(S)-1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,(R)-2-hydroxy-1-methylethyl, (S)-2-hydroxy-1-methylethyl,2-hydroxy-1-(hydroxymethyl)ethyl, (R)-1-hydroxybutyl,(S)-1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.

C₁-C₆-Alkoxy-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms arereplaced by one or two alkoxy groups having 1 to 6, preferably 1 to 4,in particular 1 or 2 carbon atoms, such as in methoxymethyl,(R)-1-methoxyethyl, (S)-1-methoxyethyl, 2-methoxyethyl,(R)-1-methoxypropyl, (S)-1-methoxypropyl, 2-methoxypropyl,3-methoxypropyl, (R)-2-methoxy-1-methylethyl,(S)-2-methoxy-1-methylethyl, 2-methoxy-1-(methoxymethyl)ethyl,(R)-1-methoxybutyl, (S)-1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl,4-methoxybutyl, ethoxymethyl, (R)-1-ethoxyethyl, (S)-1-ethoxyethyl,2-ethoxyethyl, (R)-1-ethoxypropyl, (S)-1-ethoxypropyl, 2-ethoxypropyl,3-ethoxypropyl, (R)-2-ethoxy-1-methylethyl, (S)-2-ethoxy-1-methylethyl,2-ethoxy-1-(ethoxymethyl)ethyl, (R)-1-ethoxybutyl, (S)-1-ethoxybutyl,2-ethoxybutyl, 3-ethoxybutyl, 4-ethoxybutyl.

Amino-C₁-C₄-alkyl is a straight-chain or branched alkyl group having 1to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or2 carbon atoms, in particular 1 or two carbon atoms, wherein onehydrogen atom is replaced by an amino group, such as in aminomethyl,2-aminoethyl.

C₁-C₆-Alkylamino-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by a C₁-C₆-alkylamino group, inparticular by a C₁-C₄-alkylamino group, such as in methylaminomethyl,ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl,n-butylaminomethyl, 2-butylaminomethyl, iso-butylaminomethyl ortert-butylaminomethyl.

Di-C₁-C₆-Alkylamino-C₁-C₄-alkyl is a straight-chain or branched alkylgroup having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by a di-C₁-C₆-Alkylamino group, inparticular by a di-C₁-C₄-alkylamino group, such as indimethylaminomethyl.

C₁-C₆-Alkylcarbonylamino-C₁-C₄-alkyl is a straight-chain or branchedalkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms,more preferably 1 or 2 carbon atoms, in particular 1 or two carbonatoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylcarbonylamino group, in particular by aC₁-C₄-alkylcarbonylamino group, such as in methylcarbonylaminomethyl,ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl,iso-propylcarbonylaminomethyl, n-butylcarbonylaminomethyl,2-butylcarbonylaminomethyl, iso-butylcarbonylaminomethyl ortert-butylcarbonylaminomethyl.

C₁-C₆-Alkylaminocarbonylamino-C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylaminocarbonylamino group, in particular by aC₁-C₄-alkylaminocarbonylamino group, such as inmethylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl,n-propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl,n-butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl,iso-butylaminocarbonylaminomethyl or tert-butylaminocarbonylaminomethyl.

Di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by adi-C₁-C₆-alkylaminocarbonylamino group, in particular by adi-C₁-C₄-alkylaminocarbonylamino group, such as indimethylaminocarbonylaminomethyl, dimethylaminocarbonylaminoethyl,dimethylaminocarbonylaminon-propyl.

C₁-C₆-Alkylsulfonylamino-C₁-C₄-alkyl is a straight-chain or branchedalkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms,more preferably 1 or 2 carbon atoms, in particular 1 or two carbonatoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylsulfonylamino group, in particular by aC₁-C₄-alkylsulfonylamino group, such as in methylsulfonylaminomethyl,ethylsulfonylaminomethyl, n-propylsulfonylaminomethyl,isopropylsulfonylaminomethyl, n-butylsulfonylaminomethyl,2-butylsulfonylaminomethyl, iso-butylsulfonylaminomethyl ortert-butylsulfonylaminomethyl.

(C₆-C₁₂-Aryl-C₁-C₆-alkyl)amino-C₁-C₄ alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by a(C₆-C₁₂-aryl-C₁-C₆-alkyl)amino group, in particular a(C₆-C₁₂-aryl-C₁-C₂-alkyl)amino group, such as in benzylaminomethyl.

C₃-C₁₂-Heterocyclyl-C₁-C₄-alkyl is a straight-chain or branched alkylgroup having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by C₃-C₁₂-heterocyclyl, such as inN-pyrrolidinylmethyl, N-piperidinylmethyl, N-morpholinylmethyl.

C₃-C₁₂-Cycloalkyl is a cycloaliphatic radical having from 3 to 12 carbonatoms. In particular, 3 to 6 carbon atoms form the cyclic structure,such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclicstructure may be unsubstituted or may carry 1, 2, 3 or 4 C₁-C₄ alkylradicals, preferably one or more methyl radicals.

Carbonyl is >C═O.

C₁-C₆-Alkylcarbonyl is a radical of the formula R—C(O)—, wherein R is analkyl radical having from 1 to 6, preferably from 1 to 4, in particular1 or 2 carbon atoms as defined herein. Examples include acetyl,propionyl, n-butyryl, 2-methylpropionyl, pivaloyl.

Halogenated C₁-C₆-alkylcarbonyl is C₁-C₆-alkylcarbonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms. Examples include fluoromethylcarbonyl,difluoromethylcarbonyl, trifluoromethylcarbonyl. Further examples are1,1,1-trifluoroeth-2-ylcarbonyl, 1,1,1-trifluoroprop-3-ylcarbonyl.

C₆-C₁₂-Arylcarbonyl is a radical of the formula R—C(O)—, wherein R is anaryl radical having from 6 to 12 carbon atoms as defined herein.Examples include benzoyl.

C₁-C₆-Alkoxycarbonyl is a radical of the formula R—O—C(O)—, wherein R isan alkyl radical having from 1 to 6, preferably from 1 to 4, inparticular 1 or 2 carbon atoms as defined herein. Examples includemethoxycarbonyl and tert-butyloxycarbonyl.

Halogenated C₁-C₆-alkoxycarbonyl is a C₁-C₆-alkoxycarbonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₆-C₁₂-Aryloxycarbonyl is a radical of the formula R—O—C(O)—, wherein Ris an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenoxycarbonyl.

Cyano is —C≡N.

Aminocarbonyl is NH₂C(O)—.

C₁-C₆-Alkylaminocarbonyl is a radical of the formula R—NH—C(O)—, whereinR is an alkyl radical having from 1 to 6, preferably from 1 to 4, inparticular 1 or 2 carbon atoms as defined herein. Examples includemethylaminocarbonyl.

(Halogenated C₁-C₄-alkyl)aminocarbonyl is a C₁-C₄-alkylaminocarbonyl asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different hydrogen atoms.

C₆-C₁₂-Arylaminocarbonyl is a radical of the formula R—NH—C(O)—, whereinR is an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylaminocarbonyl.

C₂-C₆-Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3,4, 5 or 6 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl),1-propen-1-yl, 2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl) and thelike. C₃-C₅-Alkenyl is, in particular, allyl, 1-methylprop-2-en-1-yl,2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl,4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl.

C₂-C₆-Alkynyl is a singly unsaturated hydrocarbon radical having 2, 3,4, 5 or 6 carbon atoms, e.g. ethynyl, 2-propyn-1-yl, 1-propyn-1-yl,2-propyn-2-yl and the like. C₃-C₅-Alkynyl is, in particular,2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl,4-pentyn-1-yl.

C₁-C₄-Alkylene is straight-chain or branched alkylene group having from1 to 4 carbon atoms. Examples include methylene and ethylene. A furtherexample is propylene.

C₂-C₄-Alkenylene is straight-chain or branched alkenylene group havingfrom 2 to 4 carbon atoms.

C₂-C₄-Alkynylene is straight-chain or branched alkynylene group havingfrom 2 to 4 carbon atoms. Examples include propynylene.

C₆-C₁₂-Aryl is a 6- to 12-membered, in particular 6- to 10-membered,aromatic cyclic radical. Examples include phenyl and naphthyl.

C₃-C₁₂-Arylene is an aryl diradical. Examples include phen-1,4-ylene andphen-1,3-ylene.

Hydroxy is —OH.

C₁-C₆-Alkoxy is a radical of the formula R—O—, wherein R is astraight-chain or branched alkyl group having from 1 to 6, in particular1 to 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, 2-butoxy, iso-butoxy (2-methylpropoxy),tert.-butoxy pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy,2,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy,3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutyloxy,1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,2-dimethylbutyloxy,2,3-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethylbutyloxy,2-ethylbutyloxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy,1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.

Halogenated C₁-C₆-alkoxy is a straight-chain or branched alkoxy grouphaving from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbonatoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms, such as in halogenomethoxy,dihalogenomethoxy, trihalogenomethoxy, (R)-1-halogenoethoxy,(S)-1-halogenoethoxy, 2-halogenoethoxy, 1,1-dihalogenoethoxy,2,2-dihalogenoethoxy, 2,2,2-trihalogenoethoxy, (R)-1-halogenopropoxy,(S)-1-halogenopropoxy, 2-halogenopropoxy, 3-halogenopropoxy,1,1-dihalogenopropoxy, 2,2-dihalogenopropoxy, 3,3-dihalogenopropoxy,3,3,3-trihalogenopropoxy, (R)-2-halogeno-1-methylethoxy,(S)-2-halogeno-1-methylethoxy, (R)-2,2-dihalogeno-1-methylethoxy,(S)-2,2-dihalogeno-1-methylethoxy, (R)-1,2-dihalogeno-1-methylethoxy,(S)-1,2-dihalogeno-1-methylethoxy, (R)-2,2,2-trihalogeno-1-methylethoxy,(S)-2,2,2-trihalogeno-1-methylethoxy,2-halogeno-1-(halogenomethyl)ethoxy,1-(dihalogenomethyl)-2,2-dihalogenoethoxy, (R)-1-halogenobutoxy,(S)-1-halogenobutoxy, 2-halogenobutoxy, 3-halogenobutoxy,4-halogenobutoxy, 1,1-dihalogenobutoxy, 2,2-dihalogenobutoxy,3,3-dihalogenobutoxy, 4,4-dihalogenobutoxy, 4,4,4-trihalogenobutoxy,etc. Particular examples include the fluorinated C₁-C₄ alkoxy groups asdefined, such as trifluoromethoxy.

C₁-C₆-Hydroxyalkoxy is an alkoxy radical having from 1 to 6, preferablyfrom 1 to 4 carbon atoms as defined herein, wherein one or two hydrogenatoms are replaced by hydroxy. Examples include 2-hydroxyethoxy,3-hydroxypropoxy, 2-hydroxypropoxy, 1-methyl-2-hydroxyethoxy and thelike.

C₁-C₆-Alkoxy-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4 carbonatoms, preferably 1 or 2 carbon atoms as defined herein, wherein one ortwo hydrogen atoms are replaced by one or two alkoxy radicals havingfrom 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.Examples include methoxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy,3-methoxypropoxy, 2-methoxypropoxy, 1-methyl-1-methoxyethoxy,ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy, 3-ethoxypropoxy,2-ethoxypropoxy, 1-methyl-1-ethoxyethoxy and the like.

Amino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4, preferably 1or 2 carbon atoms as defined herein, wherein one hydrogen atom isreplaced by an amino group. Examples include 2-aminoethoxy.

C₁-C₆-Alkylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4,preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogenatom is replaced by an alkylamino group having from 1 to 6, preferablyfrom 1 to 4 carbon atoms as defined herein. Examples includemethylaminomethoxy, ethylaminomethoxy, n-propylaminomethoxy,iso-propylaminomethoxy, n-butylaminomethoxy, 2-butylaminomethoxy,iso-butylaminomethoxy, tert-butylaminomethoxy, 2-(methylamino)ethoxy,2-(ethylamino)ethoxy, 2-(n-propylamino)ethoxy,2-(iso-propylamino)ethoxy, 2-(n-butylamino)ethoxy,2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy,2-(tert-butylamino)ethoxy.

Di-C₁-C₆-alkylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a dialkylamino group having from 1 to 6,preferably from 1 to 4 carbon atoms as defined herein. Examples includedimethylaminomethoxy, diethylaminomethoxy, N-methyl-N-ethylamino)ethoxy,2-(dimethylamino)ethoxy, 2-(diethylamino)ethoxy,2-(N-methyl-N-ethylamino)ethoxy.

C₁-C₆-Alkylcarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkylcarbonylamino group wherein thealkyl group has from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylcarbonylaminomethoxy,ethylcarbonylaminomethoxy, n-propylcarbonylaminomethoxy,iso-propylcarbonylaminomethoxy, n-butylcarbonylaminomethoxy,2-butylcarbonylaminomethoxy, iso-butylcarbonylaminomethoxy,tert-butylcarbonylaminomethoxy, 2-(methylcarbonylamino)ethoxy,2-(ethylcarbonylamino)ethoxy, 2-(n-propylcarbonylamino)ethoxy,2-(iso-propylcarbonylamino)ethoxy, 2-(n-butylcarbonylamino)ethoxy,2-(2-butylcarbonylamino)ethoxy, 2-(iso-butylcarbonylamino)ethoxy,2-(tert-butylcarbonylamino)ethoxy.

C₆-C₁₂-Arylcarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₆-C₁₂-arylcarbonylamino group as definedherein. Examples include 2-(benzoylamino)ethoxy.

C₁-C₆-Alkoxycarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkoxycarbonylamino group wherein thealkoxy group has from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methoxycarbonylaminomethoxy,ethoxycarbonylaminomethoxy, n-propoxycarbonylaminomethoxy,isopropoxycarbonylaminomethoxy, n-butoxycarbonylaminomethoxy,2-butoxycarbonylaminomethoxy, iso-butoxycarbonylaminomethoxy,tertbutoxycarbonylaminomethoxy, 2-(methoxycarbonylamino)ethoxy,2-(ethoxycarbonylamino)ethoxy, 2-(n-propoxycarbonylamino)ethoxy,2-(iso-propoxycarbonylamino)ethoxy, 2-(n-butoxycarbonylamino)ethoxy,2-(2-butoxycarbonylamino)ethoxy, 2-(isobutoxycarbonylamino)ethoxy,2-(tert-butoxycarbonylamino)ethoxy.

C₂-C₆-Alkenyloxy is a radical of the formula R—O—, wherein R is astraight-chain or branched alkenyl group having from 2 to 6, inparticular 2 to 4 carbon atoms. Examples include vinyloxy, allyloxy(2-propen-1-yloxy), 1-propen-1-yloxy, 2-propen-2-yloxy, methallyloxy(2-methylprop-2-en-1-yloxy) and the like. C₃-C₅-Alkenyloxy is, inparticular, allyloxy, 1-methylprop-2-en-1-yloxy, 2-buten-1-yloxy,3-buten-1-yloxy, methallyloxy, 2-penten-1-yloxy, 3-penten-1-yloxy,4-penten-1-yloxy, 1-methylbut-2-en-1-yloxy or 2-ethylprop-2-en-1-yloxy.

C₆-C₁₂-Aryl-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4,preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogenatom is replaced by a C₆-C₁₂-aryl group as defined herein. Examplesinclude benzyloxy.

C₁-C₆-Alkylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkylsulfonylamino group having from 1to 6, preferably from 1 to 4 carbon atoms as defined herein. Examplesinclude 2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy,2-[(2-methylpropyl)sulfonylamino]ethoxy.

(Halogenated C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by an alkylsulfonylamino grouphaving from 1 to 6, preferably from 1 to 4 carbon atoms as definedherein, wherein the alkyl group is halogenated. Examples include2-(trifluoromethylsulfonylamino)ethoxy.

C₆-C₁₂-Arylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₆-C₁₂-arylsulfonylamino group as definedherein. Examples include 2-(phenylsulfonylamino)ethoxy,2-(naphthylsulfonylamino)ethoxy.

(C₆-C₁₂-Aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by a(C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino group, preferably by a(C₆-C₁₂-aryl-C₁-C₂-alkyl)sulfonylamino group. Examples include2-(benzylsulfonylamino)ethoxy.

C₃-C₁₂-Heterocyclylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by aC₃-C₁₂-heterocyclylsulfonylamino group as defined herein. Examplesinclude 2-(pyridin-3-yl-sulfonylamino)ethoxy.

C₃-C₁₂-Heterocyclyl-C₁-C₄-alkoxy is an alkoxy radical having from 1 to4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₃-C₁₂-heterocyclyl group as definedherein. Examples include 2-(N-pyrrolidinyl)ethoxy,2-(N-morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy.

C₁-C₂-Alkylenedioxo is a radical of the formula —O—R—O—, wherein R is astraight-chain or branched alkylene group having from 1 or 2 carbonatoms as defined herein. Examples include methylenedioxo.

C₆-C₁₂-Aryloxy is a radical of the formula R—O—, wherein R is an arylgroup having from 6 to 12, in particular 6 carbon atoms as definedherein. Examples include phenoxy.

C₃-C₁₂-Heterocyclyloxy is a radical of the formula R—O—, wherein R is aC₃-C₁₂-heterocyclyl group having from 3 to 12, in particular from 3 to 7carbon atoms as defined herein. Examples include pyridin-2-yloxy.

C₁-C₆-Alkylthio is a radical of the formula R—S—, wherein R is an alkylradical having from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylthio, ethylthio, propylthio,butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio,3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio,2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio,2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio,1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio,1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl.

Halogenated C₁-C₆-alkylthio is a radical of the formula R—S—, wherein Ris a halogenated alkyl radical having from 1 to 6, preferably from 1 to4 carbon atoms as defined herein. Examples include halogenomethylthio,dihalogenomethylthio, trihalogenomethylthio, (R)-1-halogenoethylthio,(S)-1-halogenoethylthio, 2-halogenoethylthio, 1,1-dihalogenoethylthio,2,2-dihalogenoethylthio, 2,2,2-trihalogenoethylthio,(R)-1-halogenopropylthio, (S)-1-halogenopropylthio,2-halogenopropylthio, 3-halogenopropylthio, 1,1-dihalogenopropylthio,2,2-dihalogenopropylthio, 3,3-dihalogenopropylthio,3,3,3-trihalogenopropylthio, (R)-2-halogeno-1-methylethylthio,(S)-2-halogeno-1-methylethylthio, (R)-2,2-dihalogeno-1-methylethylthio,(S)-2,2-dihalogeno-1-methylethylthio,(R)-1,2-dihalogeno-1-methylethylthio,(S)-1,2-dihalogeno-1-methylethylthio,(R)-2,2,2-trihalogeno-1-methylethylthio,(S)-2,2,2-trihalogeno-1-methylethylthio,2-halogeno-1-(halogenomethyl)ethylthio,1-(dihalogenomethyl)-2,2-dihalogenoethylthio, (R)-1-halogenobutylthio,(S)-1-halogenobutylthio, 2-halogenobutylthio, 3-halogenobutylthio,4-halogenobutylthio, 1,1-dihalogenobutylthio, 2,2-dihalogenobutylthio,3,3-dihalogenobutylthio, 4,4-dihalogenobutylthio,4,4,4-trihalogenobutylthio, etc. Particular examples include thefluorinated C₁-C₄ alkylthio groups as defined, such astrifluoromethylthio.

C₁-C₆-Alkylsulfinyl is a radical of the formula R—S(O)—, wherein R is analkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl,2-methylbutylsulfinyl, 3-methylbutylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

C₁-C₆-Alkylsulfonyl is a radical of the formula R—S(O)₂—, wherein R isan alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atomsas defined herein. Examples include methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl,2-methylbutylsulfonyl, 3-methylbutylsulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

(Halogenated C₁-C₆-alkyl)sulfonyl is a C₁-C₆-alkylsulfonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₆-C₁₂-Arylsulfonyl is a radical of the formula R—S(O)₂—, wherein R isan aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylsulfonyl.

(C₆-C₁₂-Aryl-C₁-C₄-alkyl)sulfonyl is a radical of the formula R—S(O)₂—,wherein R is a C₆-C₁₂-aryl-C₁-C₄-alkyl radical, in particular aC₆-C₁₂-aryl-C₁-C₂-alkyl radical as defined herein. Examples includebenzylsulfonyl.

C₃-C₁₂-Heterocyclylsulfonyl is a radical of the formula R—S(O)₂—,wherein R is C₃-C₁₂-heterocyclyl as defined herein.

Aminosulfonyl is NH₂—S(O)₂—.

C₁-C₆-Alkylaminosulfonyl is a radical of the formula R—NH—S(O)₂— whereinR is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbonatoms as defined herein. Examples include methylaminosulfonyl,ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl,n-butylaminosulfonyl, 2-butylaminosulfonyl, iso-butylaminosulfonyl,tert-butylaminosulfonyl.

Di-C₁-C₆-alkylaminosulfonyl is a radical of the formula RR′N—S(O)₂—wherein R and R′ are independently of each other an alkyl radical havingfrom 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.Examples include dimethylaminosulfonyl, diethylaminosulfonyl,N-methyl-N-ethylaminosulfonyl.

C₆-C₁₂-Arylaminosulfonyl is a radical of the formula R—NH—S(O)₂— whereinR is an aryl radical having from 6 to 12, preferably 6 carbon atoms asdefined herein.

Amino is NH₂.

C₁-C₆-Alkylamino is a radical of the formula R—NH— wherein R is an alkylradical having from 1 to 6, in particular from 1 to 4 carbon atoms asdefined herein. Examples include methylamino, ethylamino, n-propylamino,iso-propylamino, n-butylamino, 2-butylamino, iso-butylamino,tert-butylamino.

(Halogenated C₁-C₆-alkyl)amino is a C₁-C₆-alkylamino as defined herein,wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms arereplaced by 1, 2, 3, 4 or a corresponding number of identical ordifferent halogen atoms.

Di-C₁-C₆-alkylamino is a radical of the formula RR′N— wherein R and R′are independently of each other an alkyl radical having from 1 to 6, inparticular from 1 to 4 carbon atoms as defined herein. Examples includedimethylamino, diethylamino, N-methyl-N-ethylamino.

Di-(halogenated C₁-C₆-alkyl)amino is a di-C₁-C₆-alkylamino as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₁-C₆-Alkylcarbonylamino is a radical of the formula R—C(O)—NH—, whereinR is an alkyl radical having from 1 to 6, in particular from 1 to 4carbon atoms as defined herein. Examples include acetamido(methylcarbonylamino), propionamido, n-butyramido, 2-methylpropionamido(isopropylcarbonylamino), 2,2-dimethylpropionamido and the like.

(Halogenated C₁-C₆-alkyl)carbonylamino is a C₁-C₆-alkylcarbonylamino asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different halogen atoms.

C₆-C₁₂-Arylcarbonylamino is a radical of the formula R—C(O)—NH—, whereinR is an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylcarbonylamino.

C₂-C₆-Alkenylamino is a radical of the formula R—NH—, wherein R is astraight-chain or branched alkenyl group having from 2 to 6, inparticular 2 to 4 carbon atoms. Examples include vinylamino, allylamino(2-propen-1-ylamino), 1-propen-1-ylamino, 2-propen-2-ylamino,methallylamino (2-methylprop-2-en-1-ylamino) and the like.C₃-C₅-Alkenylamino is, in particular, allylamino,1-methylprop-2-en-1-ylamino, 2-buten-1-ylamino, 3-buten-1-ylamino,methallylamino, 2-penten-1-ylamino, 3-penten-1-ylamino,4-penten-1-ylamino, 1-methylbut-2-en-1-ylamino or2-ethylprop-2-en-1-ylamino.

C₁-C₆-Alkylsulfonylamino is a radical of the formula R—S(O)₂—NH—,wherein R is an alkyl radical having from 1 to 6, in particular from 1to 4 carbon atoms as defined herein. Examples includemethylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,isopropylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino,iso-butylsulfonylamino, tert-butylsulfonylamino.

(Halogenated C₁-C₆ alkyl)sulfonylamino is a C₁-C₆-alkylsulfonylamino asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different halogen atoms.

C₆-C₁₂-Arylsulfonylamino is a radical of the formula R—S(O)₂—NH—,wherein R is an aryl radical having from 6 to 12 carbon atoms as definedherein. Examples include phenylsulfonylamino.

Nitro is —NO₂.

C₃-C₁₂-Heterocyclyl is a 3- to 12-membered heterocyclic radicalincluding a saturated heterocyclic radical, which generally has 3, 4, 5,6, or 7 ring forming atoms (ring members), an unsaturated non-aromaticheterocyclic radical, which generally has 5, 6 or 7 ring forming atoms,and a heteroaromatic radical (hetaryl), which generally has 5, 6 or 7ring forming atoms. The heterocyclic radicals may be bound via a carbonatom (C-bound) or a nitrogen atom (N-bound). Preferred heterocyclicradicals comprise 1 nitrogen atom as ring member atom and optionally 1,2 or 3 further heteroatoms as ring members, which are selected,independently of each other from O, S and N. Likewise preferredheterocyclic radicals comprise 1 heteroatom as ring member, which isselected from O, S and N, and optionally 1, 2 or 3 further nitrogenatoms as ring members.

Examples of C₃-C₁₂-heterocyclyl include:

C- or N-bound 3-4-membered, saturated rings, such as

2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl,1-azetidinyl, 2-azetidinyl, 3-azetidinyl;

C-bound, 5-membered, saturated rings, such as

tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl,tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl,tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl,tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl,1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl,tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl,1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl,tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazol-4-yl,tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl,tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl,1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl;

C-bound, 6-membered, saturated rings, such as tetrahydropyran-2-yl,tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-2-yl,piperidin-3-yl, piperidin-4-yl, tetrahydrothiopyran-2-yl,tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl,1,3-dioxan-4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl,1,3-dithian-4-yl, 1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxathian-2-yl,1,3-oxathian-4-yl, 1,3-oxathian-5-yl, 1,3-oxathian-6-yl,1,4-oxathian-2-yl, 1,4-oxathian-3-yl, 1,2-dithian-3-yl,1,2-dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl,hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl,tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl,tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl,tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl,tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl,tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl,tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl,tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl,tetrahydro-1,2-oxazin-6-yl;

N-bound, 5-membered, saturated rings, such as

tetrahydropyrrol-1-yl (pyrrolidin-1-yl), tetrahydropyrazol-1-yl,tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl,tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl;

N-bound, 6-membered, saturated rings, such as

piperidin-1-yl, hexahydropyrimidin-1-yl,hexahydropyrazin-1-yl(piperazin-1-yl), hexahydropyridazin-1-yl,tetrahydro-1,3-oxazin-3-yl, tetrahydro-1,3-thiazin-3-yl,tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-oxazin-4-yl(morpholin-1-yl),tetrahydro-1,2-oxazin-2-yl;

C-bound, 5-membered, partially unsaturated rings, such as

2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl,2,5-di-hydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl,2,3-dihydro-thien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl,2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl,2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl,2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl,4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H-pyrrol-3-yl,3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl,3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H-pyrrol-3-yl,4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl,4,5-dihydro-1H-pyrazol-5-yl, 2,5-dihydro-1H-pyrazol-3-yl,2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl,4,5-dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl,4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl,2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl,2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl,2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl,4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl,2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl,2,5-dihydroisothiazol-5-yl, 2,3-dihydroisothiazol-3-yl,2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl,4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl,4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol-2-yl,2,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl,2,3-dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl,4,5-dihydro-oxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl,2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl,2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl,4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl,4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-2-yl,2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl,2,3-dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl,2,3-dihydrothiazol-5-yl, 1,3-dioxol-2-yl, 1,3-dioxol-4-yl,1,3-dithiol-2-yl, 1,3-dithiol-4-yl, 1,3-oxathiol-2-yl,1,3-oxathiol-4-yl, 1,3-oxathiol-5-yl;

C-bound, 6-membered, partially unsaturated rings, such as

2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl,2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl,2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl,2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl,2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl,1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl,1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetra-hydropyridin-3-yl,1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl,2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl,2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl,2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl,2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl,2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl,1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl,1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetrahydropyridin-6-yl,2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl,2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl,2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl,4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl,1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl,1,4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl,2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2H-thiopyran-3-yl,2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl,1,2-dihydropyridin-2-yl, 1,2-dihydro-pyridin-3-yl,1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl,1,2-dihydro-pyridin-6-yl, 3,4-dihydropyridin-2-yl,3,4-dihydropyridin-3-yl, 3,4-dihydro-pyridin-4-yl,3,4-dihydropyridin-5-yl, 3,4-dihydropyridin-6-yl,2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl,2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl,2,5-dihydropyridin-6-yl, 2,3-dihydropyridin-2-yl,2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl,2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl,2H-5,6-dihydro-1,2-oxazin-3-yl, 2H-5,6-dihydro-1,2-oxazin-4-yl,2H-5,6-dihydro-1,2-oxazin-5-yl, 2H-5,6-dihydro-1,2-oxazin-6-yl,2H-5,6-dihydro-1,2-thiazin-3-yl, 2H-5,6-dihydro-1,2-thiazin-4-yl,2H-5,6-dihydro-1,2-thiazin-5-yl, 2H-5,6-dihydro-1,2-thiazin-6-yl,4H-5,6-dihydro-1,2-oxazin-3-yl, 4H-5,6-dihydro-1,2-oxazin-4-yl,4H-5,6-dihydro-1,2-oxazin-5-yl, 4H-5,6-dihydro-1,2-oxazin-6-yl,4H-5,6-dihydro-1,2-thiazin-3-yl, 4H-5,6-dihydro-1,2-thiazin-4-yl,4H-5,6-dihydro-1,2-thiazin-5-yl, 4H-5,6-dihydro-1,2-thiazin-6-yl,2H-3,6-dihydro-1,2-oxazin-3-yl, 2H-3,6-dihydro-1,2-oxazin-4-yl,2H-3,6-dihydro-1,2-oxazin-5-yl, 2H-3,6-dihydro-1,2-oxazin-6-yl,2H-3,6-dihydro-1,2-thiazin-3-yl, 2H-3,6-dihydro-1,2-thiazin-4-yl,2H-3,6-dihydro-1,2-thiazin-5-yl, 2H-3,6-dihydro-1,2-thiazin-6-yl,2H-3,4-dihydro-1,2-oxazin-3-yl, 2H-3,4-dihydro-1,2-oxazin-4-yl,2H-3,4-dihydro-1,2-oxazin-5-yl, 2H-3,4-dihydro-1,2-oxazin-6-yl,2H-3,4-dihydro-1,2-thiazin-3-yl, 2H-3,4-dihydro-1,2-thiazin-4-yl,2H-3,4-dihydro-1,2-thiazin-5-yl, 2H-3,4-dihydro-1,2-thiazin-6-yl,2,3,4,5-tetrahydropyridazin-3-yl, 2,3,4,5-tetrahydropyridazin-4-yl,2,3,4,5-tetrahydropyridazin-5-yl, 2,3,4,5-tetrahydropyridazin-6-yl,3,4,5,6-tetrahydropyridazin-3-yl, 3,4,5,6-tetrahydropyridazin-4-yl,1,2,5,6-tetrahydropyridazin-3-yl, 1,2,5,6-tetrahydropyridazin-4-yl,1,2,5,6-tetra-hydropyridazin-5-yl, 1,2,5,6-tetrahydropyridazin-6-yl,1,2,3,6-tetrahydro-pyridazin-3-yl, 1,2,3,6-tetrahydropyridazin-4-yl,4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4-yl,4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin-6-yl,4H-5,6-dihydro-1,3-thiazin-2-yl, 4H-5,6-dihydro-1,3-thiazin-4-yl,4H-5,6-dihydro-1,3-thiazin-5-yl, 4H-5,6-dihydro-1,3-thiazin-6-yl,3,4,5-6-tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin-4-yl,3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrahydropyrimidin-6-yl,1,2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl,1,2,3,4-tetrahydro-pyrimidin-2-yl, 1,2,3,4-tetrahydropyrimidin-4-yl,1,2,3,4-tetrahydropyrimidin-5-yl, 1,2,3,4-tetrahydropyrimidin-6-yl,2,3-dihydro-1,4-thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl,2,3-dihydro-1,4-thiazin-5-yl, 2,3-dihydro-1,4-thiazin-6-yl,2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl,2H-1,3-oxazin-6-yl, 2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl,2H-1,3-thiazin-5-yl, 2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl,4H-1,3-oxazin-4-yl, 4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl,4H-1,3-thiazin-2-yl, 4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl,4H-1,3-thiazin-6-yl, 6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl,6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl,6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl,2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl,2H-1,4-oxazin-6-yl, 2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl,2H-1,4-thiazin-5-yl, 2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl,4H-1,4-oxazin-3-yl, 4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl,1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl,1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl,1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl,1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl,1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl,1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl,1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl,3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or3,4-dihydropyrimidin-6-yl;

N-bound, 5-membered, partially unsaturated rings, such as

2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl,4,5-dihydro-1H-pyrazol-1-yl, 2,5-dihydro-1H-pyrazol-1-yl,2,3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl,2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl,2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl,2,5-dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl,2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl;

N-bound, 6-membered, partially unsaturated rings, such as

1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl,1,4-dihydro-pyridin-1-yl, 1,2-dihydropyridin-1-yl,2H-5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl,2H-3,6-dihydro-1,2-oxazin-2-yl, 2H-3,6-dihydro-1,2-thiazin-2-yl,2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1,2-thiazin-2-yl,2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6-tetrahydropyridazin-1-yl,1,2,5,6-tetrahydropyridazin-2-yl, 1,2,3,6-tetrahydropyridazin-1-yl,3,4,5,6-tetrahydropyrimidin-3-yl, 1,2,3,4-tetrahydropyrazin-1-yl,1,2,3,4-tetrahydropyrimidin-1-yl, 1,2,3,4-tetrahydropyrimidin-3-yl,2,3-dihdro-1,4-thiazin-4-yl, 2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl,4H-1,4-oxazin-4-yl, 4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl,1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl,1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl;

C-bound, 5-membered, heteroaromatic rings, such as

2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-2-yl, pyrrol-3-yl,pyrazol-3-yl, pyrazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl,imidazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl, tetrazol-5-yl;

C-bound, 6-membered, heteroaromatic rings, such as

pyridin-2-yl, pyridin-3-yl, pyridin-4-yl (4-pyridyl), pyridazin-3-yl,pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl;

N-bound, 5-membered, heteroaromatic rings, such as

pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl,1,2,4-triazol-1-yl, tetrazol-1-yl.

Heterocyclyl also includes bicyclic heterocycles, which comprise one ofthe described 5- or 6-membered heterocyclic rings and a furtheranellated, saturated or unsaturated or aromatic carbocycle, such as abenzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a furtheranellated 5- or 6-membered heterocyclic ring, this heterocyclic ringbeing saturated or unsaturated or aromatic. These include quinolinyl,isoquinolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl,benzthienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl andbenzimidazolyl. Examples of 5- or 6-membered heteroaromatic compoundscomprising an anellated cycloalkenyl ring include dihydroindolyl,dihydroindolizinyl, dihydroisoindolyl, dihydrochinolinyl,dihydroisoquinolinyl, chromenyl and chromanyl.

C₃-C₁₂-Heteroarylene is a heteroaryl diradical. Examples includepyrid-2,5-ylene and pyrid-2,4-ylene.

With respect to the compounds' capability of inhibiting glycinetransporter 1, the variables A, R, R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴,X², X³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, npreferably have the following meanings which, when taken alone or incombination, represent particular embodiments of the aminotetralinederivatives of the formula (I), (II) or any other formula disclosedherein.

In said formula (I) or (II), there may be one or more than onesubstituent R, R² and/or R³. More particularly, there may be up to 3substituents R², and up to 6 substituents R³. Preferably there is onesubstituent R and 1, 2 or 3 substituents R². Formula (I) may thus bedepicted as follows:

wherein a is 1, 2 or 3, b is 1, 2, 3, 4, 5 or 6 and c is 1. If there ismore than one radical R², these may be the same or different radicals.If there is more than one radical R³, these may be the same or differentradicals.

A is a 5- or 6-membered ring which includes two carbon atoms from thecyclopentane, cyclohexane or cycloheptane moiety to which A is fused. Amay be a homocyclic or heterocyclic ring. The ring may be saturated,unsaturated non-aromatic or aromatic. According to a particularembodiment, A is a benzene ring. As a heterocyclic ring, A may include1, 2 or 3 heteroatoms as ring member atoms, which are selected,independently of each other from N, S and O. Preferred heterocyclicrings comprise 1 nitrogen atom as ring member atom and optionally 1 or 2further heteroatoms as ring members, which are selected, independentlyof each other from O, S and N. Likewise preferred heterocyclic radicalscomprise 1 heteroatom as ring member atom, which is selected from O, Sand N, and optionally 1 or 2 further nitrogen atoms as ring memberatoms. According to a particular embodiment, A is a heterocyclic ringselected from the group consisting of the following 5- or 6-memberedheterocyclic rings:

In said formulae, hydrogen atoms are not depicted. This is meant toillustrate that the free valency of a carbon or nitrogen atom may beeither bound to a hydrogen atom, to R or to R². Accordingly, R and R²may be C- or N-bound at any position of ring A.

The skilled person will appreciate that some of the rings depicted abovemay be represented with a different structure, e.g. with hydrogen atomshaving other positions than those shown above, for instance as given inthe following structures:

Preferably, A is a heterocyclic ring selected from the group consistingof the following 5- or 6-membered heterocyclic rings:

According to a further particular embodiment, A is a heterocyclic ringselected from the group consisting of the following 5- or 6-memberedheterocyclic rings:

According to a preferred embodiment, A is a heterocyclic ring selectedfrom the group consisting of the following 5- or 6-membered heterocyclicrings:

If ring A is a 5-membered heterocyclic ring it is preferred that R isbound to G¹ or G², in particular G²:

In said formula, G¹, G² and G³ independently are —CH═, —CH₂—, —N═, —NH—,S or O, the dotted line represents a single or a double bond and R³, R⁴,X², X³, R⁵ are as defined herein.

If ring A is 6-membered heterocyclic ring it is preferred that R isbound to G¹ or G², in particular G²:

In said formula, G¹, G², G³ and G⁴ independently are —CH═, —CH₂—, —N═,—NH—, S or O, the dotted line represents a single or a double bond andR³, R⁴, X², X³, R⁵ are as defined herein.

Heterocyclic compounds having the following partial structures arepreferred:

Heterocyclic compounds having the following partial structures areparticularly preferred:

In said formulae, R and R² are as defined herein. If there is more thanone radical R², these may be the same or different radicals.

According to a particular embodiment, the partial structures depictedabove are fused with a cyclohexane moiety (i.e., n is 1). The sameapplies to the preferred and particular embodiments disclosed for ringA.

According to one embodiment, R is cyano.

Preferably, R is R¹—W-A¹-Q-Y-A²-X¹— and A, R¹, W, A¹, Q, Y, A², X¹, R²,R³, R^(4a), R^(4b), X², X³, R⁵ are as defined herein.

R¹ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl orsec-butyl, a further example being n-butyl or n-pentyl),C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopentylmethyl orcyclohexylmethyl, a further example being cyclopropylmethyl),halogenated C₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1-yl or3,3,3-trifluoroprop-1-yl), hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl(e.g. ethoxyethyl), amino-C₁-C₄-alkyl, C₁-C₆-alkylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylamino-C₁-C₄-alkyl, C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substitutedC₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl, optionally substitutedC₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl (e.g. cyclopropyl orcyclobutyl), C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, halogenatedC₁-C₆-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl, aminocarbonyl,C₁-C₆-alkylaminocarbonyl, (halogenated C₁-C₄-alkyl)aminocarbonyl,C₆-C₁₂-arylaminocarbonyl, C₂-C₆-alkenyl (e.g. prop-1,2-en-1-yl),C₂-C₆-alkynyl, optionally substituted C₆-C₁₂-aryl (e.g. phenyl, afurther example being 2-methylphenyl), hydroxy, C₁-C₆-alkoxy (e.g.tert-butyloxy), halogenated C₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, amino-C₁-C₄-alkoxy,C₁-C₆-alkylamino-C₁-C₄-alkoxy, di-C₁-C₆-alkylamino-C₁-C₄-alkoxy,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenatedC₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy,(C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated C₁-C₆-alkylthio,C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino, di-C₁-C₆-alkylamino(e.g. dimethylamino), di-(halogenated C₁-C₆-alkyl)amino,C₁-C₆-alkylcarbonylamino, (halogenated C₁-C₆-alkyl)carbonylamino,C₆-C₁₂-arylcarbonylamino, C₁-C₆-alkylsulfonylamino, (halogenatedC₁-C₆-alkyl)sulfonylamino, C₆-C₁₂-arylsulfonylamino or optionallysubstituted C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl, 2-thienyl,4-methyl-2-thienyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl,2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl,1-ethyl-1,2-diazol-4-yl, 1-difluormethyl-1,2-diazol-4-yl,2-methyl-1,3-diazol-4-yl, 1-methyl-1,3-diazol-4-yl,2-methyl-1,3-thiazol-5-yl, 2,4-dimethyl-1,3-thiazol-5-yl or3-pyrrolidinyl, a further example being 1-methyl-pyrrol-3-yl, 2-pyridyl,1-methyl-1,2-diazol-3-yl, 1-methyl-3-trifluoromethyl-1,2-diazol-4-yl,1,2-dimethyl-1,3-diazol-4-yl, 5-methylisoxazol-3-yl or1-methyl-1,2,4-triazol-3-yl). Additionally, R¹ may also betri(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl (e.g. trimethylsilylethyl).

Preferably, R¹ is C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl, isopropylor sec-butyl, a further example being n-butyl or n-pentyl),C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopentylmethyl orcyclohexylmethyl, a further example being cyclopropylmethyl),halogenated C₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1-yl or3,3,3-trifluoroprop-1-yl), C₁-C₆-alkoxy-C₁-C₄-alkyl (e.g. ethoxyethyl),amino-C₁-C₄-alkyl, C₁-C₆-alkylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl, C₆-C₁₂-aryl-C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl (e.g. cyclopropyl or cyclobutyl), C₂-C₆-alkenyl (e.g.prop-1,2-en-1-yl), optionally substituted C₆-C₁₂-aryl (e.g. phenyl),hydroxy, C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino,di-C₁-C₆-alkylamino or optionally substituted C₃-C₁₂-heterocyclyl (e.g.3-pyridyl, 2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl,5-chloro-2-thienyl, 2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl,1-methyl-1,2-diazol-4-yl, 1-ethyl-1,2-diazol-4-yl,1-difluormethyl-1,2-diazol-4-yl, 2-methyl-1,3-diazol-4-yl,1-methyl-1,3-diazol-4-yl, 2-methyl-1,3-thiazol-5-yl,2,4-dimethyl-1,3-thiazol-5-yl or 3-pyrrolidinyl). It is furtherpreferred if R¹ is tri-(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl (e.g.trimethylsilylethyl).

In particular, R¹ is C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl,isopropyl or sec-butyl, a further example being n-butyl or n-pentyl),C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopentylmethyl orcyclohexylmethyl, a further example being cyclopropylmethyl),halogenated C₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1-yl or3,3,3-trifluoroprop-1-yl), C₃-C₁₂-cycloalkyl (e.g. cyclopropyl orcyclobutyl), C₂-C₆-alkenyl (e.g. prop-1,2-en-1-yl), optionallysubstituted C₆-C₁₂-aryl (e.g. phenyl), or optionally substitutedC₃-C₁₂-heterocyclyl (e.g. 3-pyridyl, 2-thienyl, 4-methyl-2-thienyl,5-methyl-2-thienyl, 5-chloro-2-thienyl, 2,5-dimethyl-3-thienyl,1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl, 1-ethyl-1,2-diazol-4-yl,1-difluormethyl-1,2-diazol-4-yl, 2-methyl-1,3-diazol-4-yl,1-methyl-1,3-diazol-4-yl, 2-methyl-1,3-thiazol-5-yl,2,4-dimethyl-1,3-thiazol-5-yl or 3-pyrrolidinyl). In particular, R¹ mayalso be tri-(C₁-C₄-alkyl)silyl-C₁-C₄-alkyl (e.g. trimethylsilylethyl).

In connection with R¹, substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl or naphthyl, substituted with 1, 2 or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino,C₁-C₄-alkylamino, C₁-C₄-dialkylamino, morpholino and piperidinyl. Thesame applies to substituted C₆-C₁₂-aryl in substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl.

In connection with R¹, substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl, such as pyridyl, thienyl, diazolyl,quinolinyl, piperidinyl, piperazinyl or morpholinyl (pyrrolyl,isoxazolyl and triazolyl being further examples of suchC₃-C₁₂-heterocyclyl), substituted with 1, 2 or 3 substituents selectedfrom the group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxycarbonyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylsulfonyl, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino,C₆-C₁₂-arylamino and C₃-C₁₂-heterocyclyl (e.g., morpholino orpiperidinyl). The same applies to substituted C₃-C₁₂-heteroaryl insubstituted C₃-C₁₂-heteroaryl-C₁-C₄-alkyl.

According to one embodiment, W is —NR⁸— and Y is a bond. According to analternative embodiment, W is a bond and Y is —NR⁹—. According to afurther alternative embodiment, W is a bond and Y is a bond, especiallyif R¹ is a nitrogen-bound radical, e.g. nitrogen-bound heterocyclyl suchas piperazinyl or morpholinyl.

According to one embodiment, Q is —S(O)₂—. According to an alternativeembodiment, Q is —C(O)—.

According to a particular embodiment, —W-A¹-Q-Y— is —W-A¹-S(O)₂—NR⁹—,—NR⁸—S(O)₂—, -A¹-S(O)₂— or —S(O)₂—. According to a further particularembodiment, —W-A¹-Q-Y— is —W-A¹-CO—NR⁹— or —NR⁸—CO—.

A¹ is optionally substituted C₁-C₄-alkylene or a bond. In connectionwith A¹, substituted C₁-C₄-alkylene in particular includesC₁-C₄-alkylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl and cyano. Preferably, A¹ is abond. If A¹ is C₁-C₄-alkylene, W is preferably —NR⁸—.

A² is optionally substituted C₁-C₄-alkylene (e.g. 1,2-ethylene or1,3-propylene), C₁-C₄-alkylene-CO—, —CO—C₁-C₄-alkylene,C₁-C₄-alkylene-O—C₁-C₄-alkylene, C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene,optionally substituted C₆-C₁₂-arylene, optionally substitutedC₆-C₁₂-heteroarylene or a bond. Additionally, A² may be optionallysubstituted C₂-C₄-alkenylen or optionally substituted C₂-C₄-alkynylene.Preferably, A² is optionally substituted C₁-C₄-alkylene (e.g.1,2-ethylene or 1,3-propylene). More preferably, A² is C₁-C₄-alkylene(e.g. 1,2-ethylene or 1,3-propylene). Alternatively, it is preferredthat A² is optionally substituted C₆-C₁₂-arylene, in particularC₆-C₁₂-arylene selected from the group consisting of phen-1,4-ylene andphen-1,3-ylene, or optionally substituted C₆-C₁₂-heteroarylene, inparticular C₆-C₁₂-heteroarylene selected from the group consisting ofpyrid-2,5-ylene and pyrid-2,4-ylene. If A² is a bond, X¹ is preferablyoptionally substituted C₁-C₄-alkylene. Alternatively, if A² is a bond,X¹ is in particular optionally substituted C₂-C₄-alkenylene oroptionally substituted C₂-C₄-alkynylene.

In connection with A², substituted C₁-C₄-alkylene in particular includesC₁-C₄-alkylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.

In connection with A², substituted C₂-C₄-alkenylene or substitutedC₂-C₄-alkynylene in particular includes C₂-C₄-alkenylene orC₂-C₄-alkynylene substituted with 1, 2 or 3 substituents selected fromthe group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.

In connection with A², substituted C₆-C₁₂-arylene in particular includesC₆-C₁₂-arylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxycarbonyl,cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylsulfonyl, amino,C₁-C₄-alkylamino, C₁-C₄-dialkylamino, C₆-C₁₂-arylamino andC₃-C₁₂-heterocyclyl (e.g., morpholino or piperidinyl).

In connection with A², substituted C₆-C₁₂-heteroarylene in particularincludes C₆-C₁₂-heteroarylene substituted with 1, 2 or 3 substituentsselected from the group consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxycarbonyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylsulfonyl, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino,C₆-C₁₂-arylamino and C₃-C₁₂-heterocyclyl (e.g, morpholino orpiperidinyl).

X¹ is —O—, —NR¹¹—, —S— or optionally substituted C₁-C₄-alkylene (e.g.—CH₂—, a further example being 1,2-ethylene and 1,3-popylene). Inconnection with X¹, substituted C₁-C₄-alkylene in particular includesC₁-C₄-alkylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.Additionally, X¹ may be optionally substituted C₂-C₄-alkenylen oroptionally substituted C₂-C₄-alkynylene (e.g. propynylene). Inconnection with X¹, substituted C₂-C₄-alkenylene or substitutedC₂-C₄-alkynylene in particular includes C₂-C₄-alkenylene orC₂-C₄-alkynylene substituted with 1, 2 or 3 substituents selected fromthe group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.Preferably, X¹ is —O—, —NR¹¹, —S—. More preferably, X¹ is —O—.Alternatively, it is preferred if X¹ is optionally substitutedC₁-C₄-alkylene (e.g. —CH₂—, 1,2-ethylene and 1,3-popylene).

According to a particular embodiment, A² is a bond and X¹ is optionallysubstituted C₁-C₄-alkylene, optionally substituted C₂-C₄-alkenylene oroptionally substituted C₂-C₄-alkynylene.

According to a particular embodiment, R¹—W-A¹-Q-Y-A²-X¹— isR¹—S(O)₂—NH-A²-X¹—, R¹—NH—S(O)₂-A²-X¹—, R¹—C(O)—NH-A²-X¹— orR¹—NH—C(O)-A²-X¹—.

According to a particular embodiment, the structural element —Y-A²-X¹—comprises at least 2, 3 or 4 atoms in the main chain. According tofurther particular embodiments the structural element —Y-A²-X¹— has upto 4, 5 or 6 atoms in the main chain, such as 2 to 6, 2 to 5 or 2 to 4atoms in the main chain, especially 2, 3 or 4 atoms in the main chain.

According to a further particular embodiment, —Y-A²-X¹— is—C₁-C₄-alkylene-O— or —NR⁹—C₁-C₄-alkylene-O—, with —Y-A²-X¹— preferablyhaving 2 to 6, 3 to 5 and especially 4 atoms in the main chain.Particular examples of —Y-A²-X¹— include —(CH₂)₃—O— and —NR⁹—(CH₂)₂—O—.In this particular embodiment, R⁹ is as defined herein and preferably R⁹is hydrogen, C₁-C₆-alkyl (e.g. methyl or ethyl) or C₃-C₁₂-cycloalkyl(e.g. cyclopropyl), or R⁹ is C₁-C₄-alkylene that is bound to a carbonatom in A² which is C₁-C₄-alkylene.

According to a further particular embodiment, —Y-A²-X¹— is—NR⁹—C₁-C₄-alkylene- (e.g. —NH—CH₂—, a further example being —NH—(CH₂)₂—or —NH—(CH₂)₃—), with —Y-A²-X¹— preferably having 2 to 6, 2 to 5, 2 to 4and especially 2, 3 or 4 atoms in the main chain. In this particularembodiment, R⁹ is as defined herein and preferably R⁹ is hydrogen,C₁-C₆-alkyl (e.g. methyl or ethyl) or C₃-C₁₂-cycloalkyl (e.g.cyclopropyl); or R⁹ is C₁-C₄-alkylene that is bound to a carbon atom inX¹ which is C₁-C₄-alkylene. If A is a heterocyclic ring, this embodimentof —Y-A²-X¹— is particularly suitable.

According to a further particular embodiment, —Y-A²-X¹— is—NR⁹—C₂-C₄-alkenylene- or —NR⁹—C₂-C₄-alkynylene- (e.g. —NH—CH₂—C≡C—),with —Y-A²-X¹— preferably having 2 to 6, 3 to 5 and especially 4 atomsin the main chain. In this particular embodiment, R⁹ is as definedherein and preferably is R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methyl orethyl) or C₃-C₁₂-cycloalkyl (e.g. cyclopropyl or cyclobutyl). If A is aheterocyclic ring, this embodiment of —Y-A²-X¹— is particularlysuitable.

According to a further particular embodiment, —Y-A²-X¹— is—C₁-C₄-alkylene- (e.g. —(CH₂)₂—), with —Y-A²-X¹— preferably having 2 to6, 2 to 5, 2 to 4 and especially 2 atoms in the main chain. If A is aheterocyclic ring, this embodiment of —Y-A²-X¹— is particularlysuitable.

According to a further particular embodiment, the structural motif—Y-A²-X¹ as disclosed herein is bound to Q being —S(O)₂— or —C(O)—.Particular examples for this embodiment include heterocyclic compoundsof the invention wherein R is R¹—S(O)₂—Y-A²-X¹ or R¹—C(O)—Y-A²-X¹.

The radical R and in particular the radical R¹—W-A¹-Q-Y-A²-X¹— may, inprinciple, be bound to the 5-, 6-, 7- or 8-position of theaminotetraline skeleton:

In said formulae, R¹, W, A¹, Q, Y, A², X¹, R², R³, R^(4a), R^(4b), X²,X³, R⁵, n are as defined herein.

Further particular examples include heterocyclic compounds of the aboveformulae wherein the radical R¹—W-A¹-Q-Y-A²-X¹— is replaced by theradical —CN.

Aminotetraline derivatives having the radical R¹—W-A¹-Q-Y-A²-X¹— (or theradical —CN) in the 5-, 6-, 7-position are preferred.

Particularly preferred are aminotetraline derivatives having the radicalR¹—W-A¹-Q-Y-A²-X¹— (or the radical —CN) in the 7-position.

In addition to the radical R¹—W-A¹-Q-Y-A²-X¹— (or the radical —CN), theaminotetraline derivatives of the invention may have one or more thanone further substituent bound to the ring A. In these positions, theskeleton of the aminotetraline derivatives may thus be substituted withone or more than one radical R². If there is more than one radical R²,these may be the same or different radicals. In particular, in 5-, 6-,7- and/or 8-position, the aminotetraline skeleton may be substitutedwith one or more than one radical R². The aminotetraline derivatives ofthe invention may therefore be represented by one of the followingformulae:

or by corresponding formulae wherein the radical R¹—W-A¹-Q-Y-A²-X¹— isreplaced by the radical —CN,

wherein R^(2a), R^(2b), R^(2c), R^(2d) independently have one of themeanings given for R², and R¹, W, A¹, Q, Y, A², X¹, R², R³, R^(4a),R^(4b), X², X³, R⁵, n are as defined herein.

R² is hydrogen, halogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, —CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionallysubstituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenatedC₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally substitutedC₃-C₁₂-heterocyclyl, or two radicals R² together with the ring atoms ofA to which they are bound form a 5- or 6 membered ring.

An optionally substituted 5- or 6-membered ring that is formed by tworadicals R² together with the ring atoms of A to which they are boundis, for instance, a benzene ring.

In connection with R², substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl, substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen and C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

In connection with R², substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl, such as morpholinyl, pyrrolidinyl andpiperidinyl, substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, cyano,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

Preferably, R² is hydrogen, halogen or C₁-C₆-alkoxy. In particular, R²is hydrogen.

According to a particular embodiment, the aminotetraline derivatives ofthe invention have one of the following formulae:

or by corresponding formulae wherein the radical R¹—W-A¹-Q-Y-A²-X¹— isreplaced by the radical —CN,wherein R¹, W, A¹, Q, Y, A², X¹, R², R³, R^(4a), R^(4b), X², X³, R⁵, nare as defined herein.

In 1-, 2, -3-, 4- and/or 5-position, the aminotetraline derivatives ofthe invention may be substituted with one or more than one radical R³.If there is more than one radical R³, these may be the same or differentradicals. The aminotetraline derivatives of the invention may thereforebe represented by the following formula:

wherein R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), R^(3f) independentlyhave one of the meanings given for R³, and A, R, R², R³, R^(4a), R^(4b),X², X³, R⁵, n are as defined herein.

According to a particular embodiment, the aminotetraline derivatives ofthe invention have one of the following formulae:

wherein R^(3a), R^(3b), R^(3f) independently have the meaning of R³ andA, R, R², R³, R^(4a), R^(4b), X², X³, R⁵, n are as defined herein.

R³ is hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, or two radicals R³together with the carbon atom to which they are attached form a carbonylgroup.

Preferably, R³ is hydrogen or C₁-C₆-alkyl. In particular, R³ ishydrogen.

R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl orisopropyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl),halogenated C₁-C₄-alkyl (e.g. 2-fluoroethyl or 2,2,2-trifluoroethyl),hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl, CH₂CN,—CHO, C₁-C₄-alkylcarbonyl (e.g. methylcarbonyl or isopropylcarbonyl, afurther example being ethylcarbonyl), (halogenated C₁-C₄-alkyl)carbonyl(e.g. fluoromethylcarbonyl, difluoromethylcarbonyl ortrifluoromethylcarbonyl, a further example being1,1,1-trifluoroeth-2-ylcarbonyl or 1,1,1-trifluoroprop-3-ylcarbonyl),C₆-C₁₂-arylcarbonyl (e.g. phenylcarbonyl), C₁-C₄-alkoxycarbonyl (e.g.ethoxycarbonyl or tert-butyloxycarbonyl), C₆-C₁₂-aryloxycarbonyl (e.g.phenoxycarbonyl), C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂,—C(═NH)NHCN, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO orC₃-C₁₂-heterocyclyl.

Preferably, R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl,n-propyl or isopropyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g.cyclopropylmethyl), halogenated C₁-C₄-alkyl (e.g. 2-fluoroethyl or2,2,2-trifluoroethyl), amino-C₁-C₄-alkyl, CH₂CN, C₁-C₄-alkylcarbonyl(e.g. methylcarbonyl or isopropylcarbonyl), (halogenatedC₁-C₄-alkyl)carbonyl (e.g. fluoromethylcarbonyl, difluoromethylcarbonylor trifluoromethylcarbonyl), C₆-C₁₂-arylcarbonyl (e.g. phenylcarbonyl),C₁-C₄-alkoxycarbonyl (e.g. ethoxycarbonyl or tert-butyloxycarbonyl),C₆-C₁₂-aryloxycarbonyl (e.g. phenoxycarbonyl), —C(═NH)NH₂, —C(═NH)NHCN,C₁-C₆-alkylsulfonyl, amino, —NO or C₃-C₁₂-heterocyclyl. It is furtherpreferred if R¹ is —CHO.

In particular, R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl,n-propyl or isopropyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g.cyclopropylmethyl), halogenated C₁-C₄-alkyl (e.g. 2-fluoroethyl or2,2,2-trifluoroethyl), C₁-C₄-alkylcarbonyl (e.g. methylcarbonyl orisopropylcarbonyl), (halogenated C₁-C₄-alkyl)carbonyl (e.g.fluoromethylcarbonyl, difluoromethylcarbonyl ortrifluoromethylcarbonyl), C₆-C₁₂-arylcarbonyl (e.g. phenylcarbonyl),C₁-C₄-alkoxycarbonyl (e.g. ethoxycarbonyl or tert-butyloxycarbonyl),C₆-C₁₂-aryloxycarbonyl (e.g. phenoxycarbonyl). In particular, R^(4a) mayalso be —CHO.

R^(4b) is hydrogen, C₁-C₆-alkyl (e.g. methyl, a further example beingethyl), halogenated C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl, CH₂CN, —CHO,C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl,C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂, —C(═NH)NHCN,C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO orC₃-C₁₂-heterocyclyl.

Preferably, R^(4b) is hydrogen, C₁-C₆-alkyl (e.g. methyl, a furtherexample being ethyl).

Alternatively, R^(4a), R^(4b) together are optionally substitutedC₁-C₆-alkylene (e.g. 1,4-butylene, a further example being1,3-propylene, 2-fluoro-but-1,4-ylene or 1-oxo-but-1,4-ylene), whereinone —CH₂— of C₁-C₄-alkylene may be replaced by an oxygen atom (e.g.—CH₂—CH₂—O—CH₂—CH₂—) or —NR¹⁶.

X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond. Preferably, X² is>CR^(12a)R^(12b).

X³ is —O—, —S—, >CR^(13a)R^(13b) or a bond. Preferably, X³ is a bond.

Thus, it is preferred if X² is >CR^(12a)R^(12b) and X³ is a bond.

R^(12a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy. Preferably, R^(12a) is hydrogen or C₁-C₆-alkyl.

R^(13a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy. Preferably, R^(13a) is hydrogen or C₁-C₆-alkyl.

In connection with R^(12a) and R^(13a), substituted C₁-C₆-alkyl inparticular includes C₁-C₆-alkyl substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen, hydroxy, C₁-C₄-alkoxy andamino.

In connection with R^(12a) and R^(13a), substituted C₆-C₁₂-aryl inparticular includes C₆-C₁₂-aryl, such as phenyl, substituted with 1, 2or 3 substituents selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

R^(12b) is hydrogen or C₁-C₆-alkyl. According to a particularembodiment, R^(12b) is hydrogen.

R^(13b) is hydrogen or C₁-C₆-alkyl. According to a particularembodiment, R^(13b) is hydrogen.

Alternatively, R^(12a) and R^(12b), or R^(13a) and R^(13b), together aretogether are carbonyl or, preferably, optionally substitutedC₁-C₄-alkylene (e.g. 1,3-propylene), wherein one —CH₂— of C₁-C₄-alkylenemay be replaced by an oxygen atom or —NR¹⁴—.

In connection with R^(12a) and R^(12b), or R^(13a) and R^(13b),substituted C₁-C₄-alkylene in particular includes C₁-C₄-alkylenesubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxyand C₁-C₄-haloalkoxy.

According to a particular embodiment, R^(12a) is C₁-C₆-alkyl and R^(12b)is hydrogen or C₁-C₆-alkyl, or R^(13a) is C₁-C₆-alkyl and R^(13b) ishydrogen or C₁-C₆-alkyl.

According to a further particular embodiment, R^(12a) is hydrogen andR^(12b) is hydrogen, or R^(13a) is hydrogen and R^(13b) is hydrogen.

According to a further particular embodiment, R^(12a) and R^(12b)together are optionally substituted 1,3-propylene, or R^(13a) andR^(13b) together are optionally substituted 1,3-propylene.

R⁵ is optionally substituted C₆-C₁₂-aryl (e.g. phenyl, 3-chlorophenyl,3,4-dichlorophenyl or 2,4-dichlorophenyl, a further example being2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl;3-cyanophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl),optionally substituted C₃-C₁₂-cycloalkyl (e.g. cyclohexyl) or optionallysubstituted C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₃-C₁₂-cycloalkyl in particularincludes C₃-C₁₂-cycloalkyl, such as cyclopropyl or cyclohexyl,substituted with 1, 2 or 3 substituents selected from the groupconsisting of halogen, optionally substituted C₁-C₆-alkyl, halogenatedC₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy, halogenated C₁-C₆-alkoxy, amino,C₁-C₆-alkylamino, di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl, substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen (e.g. F, Cl, Br),optionally substituted C₁-C₆-alkyl (e.g. methyl), halogenatedC₁-C₆-alkyl (e.g. trifluoromethyl), CN, hydroxy, C₁-C₆-alkoxy (e.g.methoxy), halogenated C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen, optionally substitutedC₁-C₆-alkyl, halogenated C₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy,halogenated C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylaminoand C₃-C₁₂-heterocyclyl.

In connection with R⁵, C₃-C₁₂-heterocyclyl in particular isC₃-C₁₂-heteroaryl.

Preferably, R⁵ is optionally substituted C₆-C₁₂-aryl, in particular asin the aminotetraline derivatives of the formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³, n are as defined herein,andR^(15a), R^(15b), R^(15c), R^(15d), R^(15e) independently are hydrogen,halogen (e.g. F, Cl or Br), optionally substituted C₁-C₆-alkyl (e.g.methyl), halogenated C₁-C₆-alkyl (e.g. trifluoromethyl), CN, hydroxy,C₁-C₆-alkoxy (e.g. methoxy), amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino or C₃-C₁₂-heterocyclyl.

According to a particular embodiment, the invention relates toaminotetralin derivatives of the formula:

wherein A, R, R², R³, R^(4a), R^(4b), R⁵, n are as defined herein, R⁵preferably being optionally substituted aryl and in particularoptionally substituted phenyl as disclosed herein.

In connection with R⁵ or R^(15a), R^(15b), R^(15c), R^(15d), R^(15e),substituted C₁-C₆-alkyl in particular includes C₁-C₆-alkyl, especiallyC₁-C₄-alkyl, substituted with 1, 2 or 3 substituents selected from thegroup consisting of hydroxy, C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl (e.g. morpholinyl orpiperidinyl).

According to a particular embodiment, R^(15a), R^(15b), R^(15d),R^(15e), are hydrogen and R^(15c) is different from hydrogen(para-mono-substitution).

According to a further particular embodiment, R^(15a), R^(15c), R^(15d),R^(15e), are hydrogen and R^(15b) is different from hydrogen(meta-mono-substitution).

In connection with R^(15a), R^(15b), R^(15c), R^(15d), R^(15e),C₃-C₁₂-heterocyclyl in particular includes morpholinyl, imidazolyl andpyrazolyl.

The index n is 0, 1 or 2. According to a particular embodiment, n is 1.

R⁶ is hydrogen or C₁-C₆-alkyl. Preferably, R⁶ is hydrogen.

R⁷ is hydrogen or C₁-C₆-alkyl. Preferably, R⁷ is hydrogen.

R⁸ is hydrogen or C₁-C₆-alkyl. Preferably, R⁸ is hydrogen.

R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methyl or ethyl), C₃-C₁₂-cycloalkyl(e.g. cyclopropyl), amino-C₁-C₆-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl or C₃-C₁₂-heterocyclyl (e.g. 3-azetidinyl).Preferably, R⁹ is hydrogen or C₁-C₆-alkyl (e.g. methyl or ethyl).

According to a particular embodiment, R⁹ and R¹ together areC₁-C₄-alkylene (e.g. 1,3-propylene, a further example being1,2-ethylene) so as that R⁹ and R¹ together with the atom in Q to whichR¹ is bound and the nitrogen atom to which R⁹ is bound form anheterocyclic ring having, in particular, 4, 5 or 6 ring member atoms(including the nitrogen atom and Q). With W and A¹ both being a bond,such a ring may be represented by the following partial structure:

wherein Q is as defined herein (e.g. S(O)₂) and n is 0, 1, 2, 3 or 4.

According to a further particular embodiment, R⁹ is C₁-C₄-alkylene (e.g.methylene or 1,3-propylene) that is bound to a carbon atom in A² and A²is C₁-C₄-alkylene so that R⁹ and at least part of A² together with thenitrogen atom to which R⁹ is bound form an N-containing heterocyclicring having, in particular, 4, 5, 6 or 7 ring member atoms (includingthe nitrogen atom). Such a ring may be represented by the followingpartial structure:

wherein R¹, W, A¹, Q and X¹ are as defined herein, p is 1 or 2, r is 0,1 or 2 and q is 0, 1 or 2. In this particular embodiment, X¹ preferablyis —O—. Particular combinations of p, r and q include p=1, r=0, q=1; andp=1, r=0, q=0. Alternatively, p is 0, r is 3 and q is 1, with X¹preferably being —O—.

According to a further particular embodiment, R⁹ is C₁-C₄-alkylene (e.g.methylene or 1,3-propylene) that is bound to a carbon atom in X¹ and X¹is C₁-C₄-alkylene (e.g. 1,2-ethylene) so that R⁹ and at least part of X¹together with the nitrogen atom to which R⁹ is bound form anN-containing heterocyclic ring having, in particular, 4, 5, 6 or 7 ringmember atoms (including the nitrogen atom). With A² being a bond, such aring may be represented by the following partial structure:

wherein R¹, W, A¹, Q and X¹ are as defined herein, p is 1 or 2, r is 0,1 or 2 and q is 0, 1 or 2. Particular combinations of p, r and q includep=1, r=0, q=0.

R¹⁰ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl. Preferably, R¹⁰ ishydrogen.

R¹¹ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁰ is hydrogen.

Alternatively, R⁹, R¹¹ together are C₁-C₄-alkylene (e.g. ethylene).

R¹⁴ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁴ is hydrogen.

R¹⁵ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁵ is hydrogen.

R¹⁶ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁶ is hydrogen.

Particular embodiments of aminotetraline derivatives of the inventionresult if

-   A is a 5- or 6-membered ring;-   R is R¹—W-A¹-Q-Y-A²-X¹— or —CN;-   R¹ is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl,    halogenated C₁-C₆-alkyl, hydroxy-C₁-C₄-alkyl,    C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,    C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,    C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,    C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,    C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,    di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,    C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substituted    C₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substituted    C₆-C₁₂-aryl-C₁-C₄-alkyl, optionally substituted    C₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl,    C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, halogenated    C₁-C₆-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl, aminocarbonyl,    C₁-C₆-alkylaminocarbonyl, (halogenated C₁-C₄-alkyl)aminocarbonyl,    C₆-C₁₂-arylaminocarbonyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionally    substituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenated    C₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy,    amino-C₁-C₄-alkoxy, C₁-C₆-alkylamino-C₁-C₄-alkoxy,    di-C₁-C₆-alkylamino-C₁-C₄-alkoxy,    C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,    C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,    C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy,    C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenated    C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,    C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy,    (C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,    C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₄-alkoxy,    C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,    C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated    C₁-C₆-alkylthio, C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino,    di-C₁-C₆-alkylamino, di-(halogenated C₁-C₆-alkyl)amino,    C₁-C₆-alkylcarbonylamino, (halogenated C₁-C₆-alkyl)carbonylamino,    C₆-C₁₂-arylcarbonylamino, C₁-C₆-alkylsulfonylamino, (halogenated    C₁-C₆-alkyl)sulfonylamino, C₆-C₁₂-arylsulfonylamino or optionally    substituted C₃-C₁₂-heterocyclyl;-   W is —NR⁸— or a bond;-   A¹ is optionally substituted C₁-C₄-alkylene or a bond;-   Q is —S(O)₂— or —C(O)—;-   Y is —NR⁹— or a bond;-   A² is optionally substituted C₁-C₄-alkylene, C₁-C₄-alkylene-CO—,    —CO—C₁-C₄-alkylene, C₁-C₄-alkylene-O—C₁-C₄-alkylene,    C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene, optionally substituted    C₆-C₁₂-arylene, optionally substituted C₆-C₁₂-heteroarylene or a    bond;-   X¹ is —O—, —NR¹¹—, —S—, optionally substituted C₁-C₄-alkylene;-   R² is hydrogen, halogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,    hydroxy-C₁-C₄-alkyl, CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionally    substituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenated    C₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,    C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,    C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally    substituted C₃-C₁₂-heterocyclyl, or two radicals R² together with    the ring atoms of A to which they are bound form a 5- or 6 membered    ring;-   R³ is hydrogen, halogen, C₁-C₆-alkyl or C₁-C₆-alkoxy, or two    radicals R³ together with the carbon atom to which they are attached    form a carbonyl group;-   R^(4a) is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl,    halogenated C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,    C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl, CH₂CN, —CHO,    C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,    C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl,    C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂, —C(═NH)NHCN,    C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO or    C₃-C₁₂-heterocyclyl;-   R^(4b) is hydrogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,    hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,    CH₂CN, —CHO, C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,    C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl,    C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂, —C(═NH)NHCN,    C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO or    C₃-C₁₂-heterocyclyl; or-   R^(4a), R^(4b) together are optionally substituted C₁-C₆-alkylene,    wherein one —CH₂— of C₁-C₄-alkylene may be replaced by an oxygen    atom or —NR¹⁸;-   X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond;-   X³ is —O—, —NR⁷—, —S—, >CR^(13a)R^(13b) or a bond;-   R⁵ is optionally substituted C₆-C₁₂-aryl, optionally substituted    C₃-C₁₂-cycloalkyl or optionally substituted C₃-C₁₂-heterocyclyl;-   n is 0, 1 or 2;-   R⁶ is hydrogen or C₁-C₆-alkyl;-   R⁷ is hydrogen or C₁-C₆-alkyl;-   R⁸ is hydrogen or C₁-C₆-alkyl;-   R⁹ is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl, amino-C₁-C₆-alkyl,    optionally substituted C₆-C₁₂-aryl-C₁-C₄-alkyl; or-   R⁹, R¹ together are C₁-C₄-alkylene; or-   R⁹ is C₁-C₄-alkylene that is bound to a carbon atom in A² and A² is    C₁-C₄-alkylene or to a carbon atom in X¹ and X¹ is C₁-C₄-alkylene;-   R¹⁰ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl;-   R¹¹ is hydrogen or C₁-C₆-alkyl, or-   R⁹, R¹¹ together are C₁-C₄-alkylene,-   R^(12a) is hydrogen, optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,    C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl    or hydroxy;-   R^(12b) is hydrogen or C₁-C₆-alkyl, or-   R^(12a), R^(12b) together are carbonyl or optionally substituted    C₁-C₄-alkylene, wherein one —CH₂— of C₁-C₄-alkylene may be replaced    by an oxygen atom or —NR¹⁴—;-   R^(13a) is hydrogen, optionally substituted C₁-C₆-alkyl,    C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,    C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl    or hydroxy;-   R^(13b) is hydrogen or C₁-C₆-alkyl, or-   R^(13a), R^(13b) together are carbonyl or optionally substituted    C₁-C₄-alkylene, wherein one —CH₂— of C₁-C₄-alkylene may be replaced    by an oxygen atom or —NR¹⁵—;-   R¹⁴ is hydrogen or C₁-C₆-alkyl;-   R¹⁵ is hydrogen or C₁-C₆-alkyl; and-   R¹⁶ is hydrogen or C₁-C₆-alkyl,    or if one or more of said variables A, R, R¹, W, A¹, Q, Y, A², X¹,    R², R³, R⁴, X², X³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,    R¹⁵, R¹⁶, n are defined more precisely as disclosed herein.

Further particular embodiments of aminotetraline derivatives of theinvention result if

-   A is a benzene ring;-   R is R¹—W-A¹-Q-Y-A²-X¹—;-   R¹ is C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,    sec-butyl, n-pentyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g.    cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl), halogenated    C₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1-yl,    3,3,3-trifluoroprop-1-yl), tri-(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl (e.g.    trimethylsilylethyl), C₁-C₆-alkoxy-C₁-C₄-alkyl (e.g. ethoxyethyl),    C₃-C₁₂-cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl),    C₂-C₆-alkenyl (e.g. prop-1,2-en-1-yl), optionally substituted    C₆-C₁₂-aryl (e.g. phenyl, 2-methylphenyl), or optionally substituted    C₃-C₁₂-heterocyclyl (e.g. 1-methyl-pyrrol-3-yl, 2-pyridyl,    3-pyridyl, 2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl,    5-chloro-2-thienyl, 2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl,    1-methyl-1,2-diazol-3-yl, 1-methyl-1,2-diazol-4-yl,    1-ethyl-1,2-diazol-4-yl, 1-difluormethyl-1,2-diazol-4-yl,    1-methyl-3-trifluoromethyl-1,2-diazol-4-yl,    2-methyl-1,3-diazol-4-yl, 1-methyl-1,3-diazol-4-yl,    1,2-dimethyl-1,3-diazol-4-yl, 5-methylisoxazol-3-yl,    2-methyl-1,3-thiazol-5-yl, 2,4-dimethyl-1,3-thiazol-5-yl,    1-methyl-1,2,4-triazol-3-yl, 3-pyrrolidinyl);-   W is a bond;-   A¹ is a bond;-   Q is —S(O)₂— or —C(O)—;-   Y is —NR⁹— or a bond;-   A² is C₁-C₄-alkylene (e.g. 1,2-ethylene, 1,3-propylene) or a bond;-   X¹ is —O— or optionally substituted C₁-C₄-alkylene (e.g. methylene,    1,2-ethylene, 1,3-propylene) or C₂-C₄-alkynylene (e.g.    prop-1,2-yn-1,3-ylene);-   R² is hydrogen;-   R³ is hydrogen;-   R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl,    isopropyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl),    halogenated C₁-C₄-alkyl (e.g. 2-fluoroethyl, 2,2,2-trifluoroethyl),    —CHO, C₁-C₄-alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl,    isopropylcarbonyl), (halogenated C₁-C₄-alkyl)carbonyl (e.g.    fluoromethylcarbonyl, difluoromethylcarbonyl,    trifluoromethylcarbonyl, 1,1,1-trifluoroeth-2-ylcarbonyl,    1,1,1-trifluoroprop-3-ylcarbonyl), C₆-C₁₂-arylcarbonyl (e.g.    phenylcarbonyl), C₁-C₄-alkoxycarbonyl (e.g. ethoxycarbonyl,    tert-butyloxycarbonyl), C₆-C₁₂-aryloxycarbonyl (e.g.    phenoxycarbonyl);-   R^(4b) is hydrogen or C₁-C₆-alkyl (e.g. methyl, ethyl); or-   R^(4a), R^(4b) together are optionally substituted C₁-C₆-alkylene    (e.g. 1,3-propylene, 1,4-butylene, 2-fluoro-but-1,4-ylene,    1-oxo-but-1,4-ylene), wherein one —CH₂— of C₁-C₄-alkylene may be    replaced by an oxygen atom (e.g. —CH₂—CH₂—O—CH₂—CH₂—);-   X² is CR^(12a)R^(12b);-   X³ is a bond;-   R⁵ is optionally substituted phenyl (e.g. phenyl, 2-fluorophenyl,    2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-cyanophenyl,    3-methylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,    4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,    3,5-difluorophenyl, 3-fluoro-5-chlorophenyl,    3-chloro-4-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl) or    optionally substituted C₃-C₁₂-cycloalkyl (e.g. cyclohexyl);-   n is 1;-   R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl) or    C₃-C₁₂-cycloalkyl [cyclopropyl), or-   R⁹, R¹ together are C₁-C₄-alkylene (e.g. 1,3-propylene); or-   R⁹ is C₁-C₄-alkylene (e.g. methylene, 1,3-propylene) that is bound    to a carbon atom in A² and A² is C₁-C₄-alkylene (e.g. 1,2-ethylene,    1,3-propylene) or to a carbon atom in X¹ and X¹ is C₁-C₄-alkylene    (e.g. 1,2-ethylene);-   R^(12a) is hydrogen; and-   R^(12b) is hydrogen.

Further particular embodiments of aminotetraline derivatives of theinvention result if

-   A is a benzene ring;-   R is R¹—W-A¹-Q-Y-A²-X¹—;-   R¹ is C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or    sec-butyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopentylmethyl or    cyclohexylmethyl), halogenated C₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl,    3-chloroprop-1-yl or 3,3,3-trifluoroprop-1-yl), C₃-C₁₂-cycloalkyl    (e.g. cyclopropyl or cyclobutyl), C₂-C₆-alkenyl (e.g.    prop-1,2-en-1-yl), optionally substituted C₆-C₁₂-aryl (e.g. phenyl),    or optionally substituted C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl,    2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl,    5-chloro-2-thienyl, 2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl,    1-methyl-1,2-diazol-4-yl, 1-ethyl-1,2-diazol-4-yl,    1-difluormethyl-1,2-diazol-4-yl, 2-methyl-1,3-diazol-4-yl,    1-methyl-1,3-diazol-4-yl, 2-methyl-1,3-thiazol-5-yl,    2,4-dimethyl-1,3-thiazol-5-yl or 3-pyrrolidinyl);-   W is a bond;-   A¹ is a bond;-   Q is —S(O)₂— or —C(O)—;-   Y is —NR⁹— or a bond;-   A² is C₁-C₄-alkylene (e.g. methylene or 1,3-propylene) or a bond;-   X¹ is —O— or optionally substituted C₁-C₄-alkylene (e.g. methylene);-   R² is hydrogen;-   R³ is hydrogen;-   R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl or    isopropyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl),    halogenated C₁-C₄-alkyl (e.g. 2-fluoroethyl or    2,2,2-trifluoroethyl), C₁-C₄-alkylcarbonyl (e.g. methylcarbonyl or,    isopropylcarbonyl), (halogenated C₁-C₄-alkyl)carbonyl (e.g.    fluoromethylcarbonyl, difluoromethylcarbonyl or    trifluoromethylcarbonyl), C₆-C₁₂-arylcarbonyl (e.g. phenylcarbonyl),    C₁-C₄-alkoxycarbonyl (e.g. ethoxycarbonyl or tert-butyloxycarbonyl),    C₆-C₁₂-aryloxycarbonyl (e.g. phenoxycarbonyl);-   R^(4b) is hydrogen or C₁-C₆-alkyl (e.g. methyl);-   X² is CR^(12a)R^(12b);-   X³ is a bond;-   R⁵ is optionally substituted phenyl (e.g. phenyl, 3-chlorophenyl,    3,4-dichlorophenyl or 2,4-dichlorophenyl);-   n is 1;-   R⁶ is hydrogen;-   R⁷ is hydrogen;-   R⁸ is hydrogen;-   R⁹ is hydrogen or alkyl (e.g. methyl or ethyl); or-   R⁹, R¹ together are C₁-C₄-alkylene (e.g. 1,3-propylene); or-   R⁹ is C₁-C₄-alkylene (e.g. methylene or 1,3-propylene) that is bound    to a carbon atom in A² and A² is C₁-C₄-alkylene;-   R¹⁰ is hydrogen;-   R¹¹ is hydrogen;-   R^(12a) is hydrogen; and-   R^(12b) is hydrogen.

Particular compounds of the present invention are the aminotetralinederivatives disclosed in preparation examples and physiologicallytolerated acid addition salts thereof. These include for eachpreparation example the exemplified compound as well as thecorresponding free base and any other physiologically tolerated acidaddition salts of the free base (if the exemplified compound is a salt),or any physiologically tolerated acid addition salt of the free base (ifthe exemplified compound is a free base). These further includeenantiomers, diastereomers, tautomers and any other isomeric forms ofsaid compounds, be they explicitly or implicitly disclosed.

The compounds of the formula (I) can be prepared by analogy to methodswhich are well known in the art. Suitable methods for the preparation ofcompounds of formula (I) is outlined in the following schemes.

The process depicted in scheme 1 is useful for obtainingaminotetralines, wherein X¹ is —O— or —S—.

As shown in scheme 1, the compound of general formula I readilyundergoes enamine alkylation to give the compound of general formula 3.

In scheme 1, the variables X², X³, R⁵ are as defined herein and L asuitable protecting group (e.g. L=Me). The process depicted in scheme 1is also useful for obtaining aminotetralines, wherein X is optionallysubstituted alkylene. In this case, L is a group that represents, or canbe converted into, the desired side chain R¹—W-A¹-Q-Y-A²-.

Alternatively, compounds of formula 3 can be prepared as described inscheme 2.

As shown in scheme 2, the compound of general formula 4 readilyundergoes alkylation to give the compound of general formula 5.Conversion to the acid chloride and subsequent ring closure withethylene in the presence of a Lewis acid (e.g. AlCl₃) affords compound 3(e.g. J. Het. Chem., 23 (2), 343, 1986 and Bioorg. Med. Chem. Let, 17(22), 6160, 2007) The variables X², X³, R⁵ are as defined herein and L,L¹ are a suitable protecting group (e.g. L, L¹=Me). Compounds 3 can befurther converted to compounds of the general formula (I).

The process depicted in scheme 3 is useful for obtainingaminotetralines, wherein X¹ is —O— or —S—, A² is optionally substitutedalkylene, Y is —NR⁹—, and Q is —S(O)₂.

In scheme 3, the variables R¹, W, A¹, R², R³, R^(4a), R^(4b), R⁵, R⁹,X², X³ are as defined herein and L² is a suitable protecting group (e.g.L²=COOEt).

The process depicted in scheme 4 is useful for obtainingaminotetralines, wherein X¹ is methylene, A² is a bond, Y is —NR⁹—, andQ is —S(O)₂.

Alternatively to triflate 19, the corresponding bromide or iodide can beused to prepare compound 20.

In scheme 4, the variables R¹, W, A¹, R², R³, R^(4a), R^(4b), R⁵, R⁹,X², X³ are as defined herein, and L³ is a suitable protecting group(e.g. L³=COO^(t)Bu).

The process depicted in scheme 5 is useful for obtainingaminotetralines, wherein X¹ is optionally substituted alkylene, A² isoptionally substituted alkylene or a bond, Y is —NR⁹—, and Q is —S(O)₂.

Instead of the trifluoroborate 66, the corresponding9-borabicyclo[3.3.1]non-9-yl derivative can be used to prepare compound26.

In scheme 5, the variables R¹, W, A¹, R², R³, R^(4a), R^(4b), R⁵, R⁹,X², X³, A² are as defined herein, and L³ is a suitable protecting group(e.g. L³=COO^(t)Bu).

The process depicted in scheme 6 is useful for obtainingaminotetralines, wherein X is —NR¹¹—, A² is optionally substitutedalkylene, Y is —NR⁹—, and Q is —S(O)₂.

In scheme 5, the variables R¹, W, A¹, R², R³, R^(4a), R^(4b), R⁵, R⁹,X², X³, A² are as defined herein, and L⁴ is a suitable protecting group.

The process depicted in the following schemes is useful for obtainingcompounds of the general formula (I) in which A is a heterocycle.

As shown in scheme 7, the compound of general formula 34 readilyundergoes condensation with dimethylformamide dimethyl acetal to givethe compound of general formula 35.

As shown in the above scheme 8, the intermediate of general formula 35reacts with various nucleophiles of general formula H₂N—NH—R in analcoholic solvent preferably methanol or ethanol at a temperature ofabout 20° to 80° C. to obtain the compounds of general formulae 36 and37. In case of monosubstituted hydrazines regioisomeric products areformed. Compounds 36 and 37 can be transformed to compounds of thegeneral formula (I) as depicted in Scheme 9.

In scheme 8, the variable R is as defined herein.

Alkylation of 38 can proceed via an enamine as described in scheme 1, orvia an enolate. Reductive amination of 39 leads to 40. Alkylation oracylation of 40 affords 41. In scheme 9, the variables R, R^(4a),R^(4b), R⁵, X², X³ are as defined herein.

As shown in scheme 10, the reaction of compound of general formula 34with hydroxyl (tosyloxy)iodobenzene gives the compound of formula 42.Reaction of compound of general formula 42 with 1,3-nucleophiles underappropriate conditions yield the compound of general formula 43. Furthertransformation to compounds of general formula 46 occurs as described inScheme 9.

In scheme 10, the variables R, R^(4a), R^(4b), R⁵, X², X³ are as definedherein.

As shown in scheme 11, the condensation of compound of general formula35 with reagent of general formula 49 and ammonia acetate in refluxingacetic acid give compound of general formula 47, which can be furthertransformed to compounds of general formula 48.

In scheme 11, the variables R, R^(4a), R^(4b), R⁵, X², X³ are as definedherein.

As shown in scheme 12, the cyclocondensation of intermediate of generalformula 35 with the 1,3-nucleophiles of general formula 50 in thepresence of suitable organic or inorganic bases such as KOH, NaOH,NaHCO3, sodium ethoxide, sodium methoxide, triethyl amine anddiisopropyl ethyl amine in an alcoholic solvent, preferably ethanol ormethanol, at a temperature of about 20° to 80° C. yield the compound ofgeneral formula 51, which can be transformed further to give compoundsof general formula 52.

In scheme 12, the variables R, R^(4a), R^(4b), R⁵, X², X³ are as definedherein.

As shown in scheme 13, the intermediate of general formula 53 readilycan undergo condensation with dimethylformamide dimethyl acetal to givethe compound of general formula 54, which reacts with variousnucleophiles of general formula H₂N—NH—R in an alcoholic solvent,preferably methanol or ethanol, at a temperature of about 20° to 80° C.to afford the compound of general formula 55 and 56. Compounds 55 and 56can be trans-formed to compounds of the general formula (I) as depictedin the previous schemes.

In scheme 13, the variables R, R^(4a), R^(4b), R⁵, X², X³ are as definedherein.

As shown in scheme 14, the reaction of compound of general formula 53with hydroxyl (tosyloxy)iodobenzene gives the compound of formula 59,which reacts with 1,3-nucleophiles under appropriate conditions to yieldthe compound of general formula 60. Further transformation to compoundsof general formula 62 occurs as described in the previous schemes.

In scheme 14, the variables R, R^(4a), R^(4b), R⁵, X², X³ are as definedherein.

As shown in scheme 15, the cyclocondensation of intermediate of generalformula 54 with the 1,3-nucleophiles of general formula 50 in thepresence of suitable organic or inorganic bases such as KOH, NaOH,NaHCO₃, sodium ethoxide, sodium methoxide, triethyl amine anddiisopropyl ethyl amine in an alcoholic solvent, preferably ethanol ormethanol, at a temperature of about 20° to 80° C. yields the compound ofgeneral formula 63, which can be transformed further to give compoundsof general formula 65 as described in the previous schemes.

In scheme 15, the variables R, R^(4a), R^(4b), R⁵, X², X³ are as definedherein.

The acid addition salts of the aminotetraline derivatives of formula (I)are prepared in a customary manner by mixing the free base with acorresponding acid, optionally in solution in an organic solvent, forexample a lower alcohol, such as methanol, ethanol or propanol, anether, such as methyl tert-butyl ether or diisopropyl ether, a ketone,such as acetone or methyl ethyl ketone, or an ester, such as ethylacetate.

The aminotetraline derivatives of formula (II)

wherein L is an amino-protecting group, Y is NR⁹, and A², X¹, R², R³,R^(4a), R^(4b), X², X³, R⁵, n are defined as above are useful asintermediates in the preparation of GlyT1 inhibitors, in particularthose of formula (I).

Suitable amino-protecting groups are well known in the art such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991.

According to a particular embodiment, L is optionally substitutedalkylcarbonyl (e.g., tert-butylcarbonyl), optionally substitutedarylcarbonyl, optionally substituted arylalkycarbonyl (e.g.,benzylcarbonyl), optionally substituted alkoxycarbonyl (e.g.,methoxycarbonyl or tert-butyloxycarbonyl), optionally substitutedaryloxycarbonyl (e.g. phenoxycarbonyl) or optionally substitutedarylalkoxycarbonyl.

The compounds of the formula (I) are capable of inhibiting the activityof glycine transporter, in particular glycine transporter 1 (GlyT1).

The utility of the compounds in accordance with the present invention asinhibiting the glycine transporter activity, in particular GlyT1activity, may be demonstrated by methodology known in the art. Forinstance, human GlyT1c expressing recombinant hGlyT1c_(—)5_CHO cells canbe used for measuring glycine uptake and its inhibition (IC₅₀) by acompound of formula (I).

Amongst the compounds of the formula (I) those are preferred whichachieve effective inhibition at low concentrations. In particular,compounds of the formula (I) are preferred which inhibit glycinetransporter 1 (GlyT1) at a level of IC₅₀<1 μMol, more preferably at alevel of IC₅₀<0.5 μMol, particularly preferably at a level of IC₅₀<0.2μMol and most preferably at a level of IC₅₀<0.1 μMol.

The compounds of the formula (I) according to the present invention arethus useful as pharmaceuticals.

The present invention therefore also relates to pharmaceuticalcompositions which comprise an inert carrier and a compound of theformula (I).

The present invention also relates to the use of the compounds of theformula (I) in the manufacture of a medicament for inhibiting theglycine transporter GlyT1, and to corresponding methods of inhibitingthe glycine transporter GlyT1.

The NMDA receptor is central to a wide range of CNS processes, and itsrole in a variety of diseases in humans or other species has beendescribed. GlyT1 inhibitors slow the removal of glycine from thesynapse, causing the level of synaptic glycine to rise. This in turnincreases the occupancy of the glycine binding site on the NMDAreceptor, which increases activation of the NMDA receptor followingglutamate release from the presynaptic terminal. Glycine transportinhibitors and in particular inhibitors of the glycine trans-porterGlyT1 are thus known to be useful in treating a variety of neurologicand psychiatric disorders. Further, glycine A receptors play a role in avariety of diseases in humans or other species. Increasing extracellularglycine concentrations by inhibiting glycine trans-port may enhance theactivity of glycine A receptors. Glycine transport inhibitors and inparticular inhibitors of the glycine transporter GlyT1 are thus usefulin treating a variety of neurologic and psychiatric disorders.

The present invention thus further relates to the use of the compoundsof the formula (I) for the manufacture of a medicament for treating aneurologic or psychiatric disorder, and to corresponding methods oftreating said disorders.

According to a particular embodiment, the disorder is associated withglycinergic or glutamatergic neurotransmission dysfunction.

According to a further particular embodiment, the disorder is one ormore of the following conditions or diseases: schizophrenia or apsychotic disorder including schizophrenia (paranoid, disorganized,catatonic or undifferentiated), schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition and substance-induced psychotic disorder, including both thepositive and the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orcognitive impairment including age related cognitive decline; anxietydisorders including acute stress disorder, agoraphobia, generalizedanxiety disorder, obsessive-compulsive disorder, panic attack, panicdisorder, post-traumatic stress disorder, separation anxiety disorder,social phobia, specific phobia, substance-induced anxiety disorder andanxiety due to a general medical condition; substance-related disordersand addictive behaviors (including substance-induced delirium,persisting dementia, persisting amnestic disorder, psychotic disorder oranxiety disorder; tolerance, dependence or withdrawal from substancesincluding alcohol, amphetamines, cannabis, cocaine, hallucinogens,inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics oranxiolytics); obesity, bulimia nervosa and compulsive eating disorders;bipolar disorders, mood disorders including depressive disorders;depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders; learning disorders,pervasive developmental disorder including autistic disorder, attentiondeficit disorders including attention-deficit hyperactivity disorder(ADHD) and conduct disorder; movement disorders, including akinesias andakinetic-rigid syndromes (including Parkinson's disease, drug-inducedparkinsonism, postencephalitic parkinsonism, progressive supranuclearpalsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification),medication-induced parkinsonism (such as neuroleptic-inducedparkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremor), Gilles de laTourette's syndrome, epilepsy, muscular spasms and disorders associatedwith muscular spasticity or weakness including tremors; dyskinesias[including tremor (such as rest tremor, postural tremor and intentiontremor), chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea and hemiballism), myoclonus (including generalised myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics), and dystonia (including generalised dystonia such asiodiopathic dystonia, drug-induced dystonia, symptomatic dystonia andparoxymal dystonia, and focal dystonia such as blepharospasm,oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis,axial dystonia, dystonic writer's cramp and hemiplegic dystonia)];urinary incontinence; neuronal damage including ocular damage,retinopathy or macular degeneration of the eye, tinnitus, hearingimpairment and loss, and brain edema; emesis; and sleep disordersincluding insomnia and narcolepsy.

According to a further particular embodiment, the disorder is pain, inparticular chronic pain and especially neuropathic pain.

Pain can be classified as acute and chronic pain. Acute pain and chronicpain differ in their etiology, pathophysiology, diagnosis and treatment.

Acute pain, which occurs following tissue injury, is self-limiting,serves as an alert to ongoing tissue damage and following tissue repairit will usually subside. There are minimal psychological symptomsassociated with acute pain apart from mild anxiety. Acute pain isnociceptive in nature and occurs following chemical, mechanical andthermal stimulation of A-delta and C-polymodal pain receptors.

Chronic pain, on the other hand, serves no protective biologicalfunction. Rather than being the symptom of tissue damage it is a diseasein its own right. Chronic pain is unrelenting and not self-limiting andcan persist for years, perhaps decades after the initial injury. Chronicpain can be refractory to multiple treatment regimes. Psychologicalsymptoms associated with chronic pain include chronic anxiety, fear,depression, sleeplessness and impairment of social interaction. Chronicnon-malignant pain is predominantly neuropathic in nature and involvesdamage to either the peripheral or central nervous systems.

Acute pain and chronic pain are caused by different neuro-physiologicalprocesses and therefore tend to respond to different types oftreatments. Acute pain can be somatic or visceral in nature. Somaticpain tends to be a well localised, constant pain and is described assharp, aching, throbbing or gnawing. Visceral pain, on the other hand,tends to be vague in distribution, paroxysmal in nature and is usuallydescribed as deep, aching, squeezing or colicky in nature. Examples ofacute pain include post-operative pain, pain associated with trauma andthe pain of arthritis. Acute pain usually responds to treatment withopioids or non-steroidal anti-inflammatory drugs.

Chronic pain, in contrast to acute pain, is described as burning,electric, tingling and shooting in nature. It can be continuous orparoxysmal in presentation. The hallmarks of chronic pain are chronicallodynia and hyperalgesia. Allodynia is pain resulting from a stimulusthat normally does not ellicit a painful response, such as a lighttouch. Hyperalgesia is an increased sensitivity to normally painfulstimuli. Primary hyperalgesia occurs immediately within the area of theinjury. Secondary hyperalgesia occurs in the undamaged area surroundingthe injury. Examples of chronic pain include complex regional painsyndrome, pain arising from peripheral neuropathies, post-operativepain, chronic fatigue syndrome pain, tension-type headache, pain arisingfrom mechanical nerve injury and severe pain associated with diseasessuch as cancer, metabolic disease, neurotropic viral disease,neurotoxicity, inflammation, multiple sclerosis or any pain arising as aconsequence of or associated with stress or depressive illness.

Although opioids are cheap and effective, serious and potentiallylife-threatening side effects occur with their use, most notablyrespiratory depression and muscle rigidity. In addition the doses ofopioids which can be administered are limited by nausea, emesis,constipation, pruritis and urinary retention, often resulting inpatients electing to receive suboptimal pain control rather than sufferthese distressing side-effects. Furthermore, these side-effects oftenresult in patients requiring extended hospitalisation. Opioids arehighly addictive and are scheduled drugs in many territories.

The compounds of formula (I) are particularly useful in the treatment ofschizophrenia, bipolar disorder, depression including unipolardepression, seasonal depression and postpartum depression, premenstrualsyndrome (PMS) and premenstrual dysphoric disorder (PDD), learningdisorders, pervasive developmental disorder including autistic disorder,attention deficit disorders including Attention-Deficit/HyperactivityDisorder, tic disorders including Tourette's disorder, anxiety disordersincluding phobia and post traumatic stress disorder, cognitive disordersassociated with dementia, AIDS dementia, Alzheimer's, Parkinson's,Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus andhearing impairment and loss are of particular importance.

Particular cognitive disorders are dementia, delirium, amnesticdisorders and cognitive impairment including age-related cognitivedecline.

Particular anxiety disorders are generalized anxiety disorder,obsessive-compulsive disorder and panic attack.

Particular schizophrenia or psychosis pathologies are paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder.

Particular neurologic disorders that can be treated with the compoundsof the formula (I) include in particular a cognitive disorder such asdementia, cognitive impairment, attention deficit hyperactivitydisorder.

Particular psychiatric disorders that can be treated with the compoundsof the formula (I) include in particular an anxiety disorder, a mooddisorder such as depression or a bipolar disorder, schizophrenia, apsychotic disorder.

Within the context of the treatment, the use according to the inventionof the compounds of the formula (I) involves a method. In this method,an effective quantity of one or more compounds or the formula (I), as arule formulated in accordance with pharmaceutical and veterinarypractice, is administered to the individual to be treated, preferably amammal, in particular a human being. Whether such a treatment isindicated, and in which form it is to take place, depends on theindividual case and is subject to medical assessment (diagnosis) whichtakes into consideration signs, symptoms and/or malfunctions which arepresent, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

As a rule, the treatment is effected by means of single or repeateddaily administration, where appropriate together, or alternating, withother drugs or drug-containing preparations.

The invention also relates to the manufacture of pharmaceuticalcompositions for treating an individual, preferably a mammal, inparticular a human being. Thus, the compounds of the formula (I) arecustomarily administered in the form of pharmaceutical compositionswhich comprise an inert carrier (e.g. a pharmaceutically acceptableexcipient) together with at least one compound according to theinvention and, where appropriate, other drugs. These compositions can,for example, be administered orally, rectally, transdermally,subcutaneously, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinalforms, such as powders, granules, tablets, in particular film tablets,lozenges, sachets, cachets, sugarcoated tablets, capsules, such as hardgelatin capsules and soft gelatin capsules, suppositories or vaginalmedicinal forms, semisolid medicinal forms, such as ointments, creams,hydrogels, pastes or plasters, and also liquid medicinal forms, such assolutions, emulsions, in particular oil-in-water emulsions, suspensions,for example lotions, injection preparations and infusion preparations,and eyedrops and eardrops. Implanted release devices can also be usedfor administering inhibitors according to the invention. In addition, itis also possible to use liposomes or microspheres.

When producing the compositions, the compounds according to theinvention are optionally mixed or diluted with one or more carriers(excipients). Carriers (excipients) can be solid, semisolid or liquidmaterials which serve as vehicles, carriers or medium for the activecompound.

Suitable carriers (excipients) are listed in the specialist medicinalmonographs. In addition, the formulations can comprise pharmaceuticallyacceptable auxiliary substances, such as wetting agents; emulsifying andsuspending agents; preservatives; antioxidants; antiirritants; chelatingagents; coating auxiliaries; emulsion stabilizers; film formers; gelformers; odor masking agents; taste corrigents; resin; hydrocolloids;solvents; solubilizers; neutralizing agents; diffusion accelerators;pigments; quaternary ammonium compounds; refatting and overfattingagents; raw materials for ointments, creams or oils; siliconederivatives; spreading auxiliaries; stabilizers; sterilants; suppositorybases; tablet auxiliaries, such as binders, fillers, glidants,disintegrants or coatings; propellants; drying agents; opacifiers;thickeners; waxes; plasticizers and white mineral oils. A formulation inthis regard is based on specialist knowledge as described, for example,in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik andangrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy,cosmetics and related fields], 4^(th) edition, Aulendorf:ECV-Editio-Cantor-Verlag, 1996.

The compounds of formula (I) may also be suitable for combination withother therapeutic agents.

Thus, the present invention also provides:

i) a combination comprising a compound of formula (I) with one or morefurther therapeutic agents;

ii) a pharmaceutical composition comprising a combination product asdefined in i) above and at least one carrier, diluent or excipient;

iii) the use of a combination as defined in i) above in the manufactureof a medicament for treating or preventing a disorder, disease orcondition as defined herein;

iv) a combination as defined in i) above for use in treating orpreventing a disorder, disease or condition as defined herein;

v) a kit-of-parts for use in the treatment of a disorder, disease orcondition as defined herein, comprising a first dosage form comprising acompound of formula (I) and one or more further dosage forms eachcomprising one or more further therapeutic agents for simultaneoustherapeutic administration,vi) a combination as defined in i) above for use in therapy;vii) a method of treatment or prevention of a disorder, disease orcondition as defined herein comprising administering an effective amountof a combination as defined in i) above;viii) a combination as defined in i) above for treating or preventing adisorder, disease or condition as defined herein.

The combination therapies of the invention may be administeredadjunctively. By adjunctive administration is meant the coterminous oroverlapping administration of each of the components in the form ofseparate pharmaceutical compositions or devices. This regime oftherapeutic administration of two or more therapeutic agents is referredto generally by those skilled in the art and herein as adjunctivetherapeutic administration; it is also known as add-on therapeuticadministration. Any and all treatment regimes in which a patientreceives separate but coterminous or overlapping therapeuticadministration of the compounds of formula (I) and at least one furthertherapeutic agent are within the scope of the current invention. In oneembodiment of adjunctive therapeutic administration as described herein,a patient is typically stabilised on a therapeutic administration of oneor more of the components for a period of time and then receivesadministration of another component.

The combination therapies of the invention may also be administeredsimultaneously. By simultaneous administration is meant a treatmentregime wherein the individual components are administered together,either in the form of a single pharmaceutical composition or devicecomprising or containing both components, or as separate compositions ordevices, each comprising one of the components, administeredsimultaneously. Such combinations of the separate individual componentsfor simultaneous combination may be provided in the form of akit-of-parts.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of compoundsof formula (I) to a patient receiving therapeutic administration of atleast one antipsychotic agent. In a further aspect, the inventionprovides the use of compounds of formula (I) in the manufacture of amedicament for adjunctive therapeutic administration for the treatmentof a psychotic disorder in a patient receiving therapeuticadministration of at least one antipsychotic agent. The inventionfurther provides compounds of formula (I) for use for adjunctivetherapeutic administration for the treatment of a psychotic disorder ina patient receiving therapeutic administration of at least oneantipsychotic agent.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of at leastone antipsychotic agent to a patient receiving therapeuticadministration of compounds of formula (I). In a further aspect, theinvention provides the use of at least one antipsychotic agent in themanufacture of a medicament for adjunctive therapeutic administrationfor the treatment of a psychotic disorder in a patient receivingtherapeutic administration of compounds of formula (I). The inventionfurther provides at least one antipsychotic agent for adjunctivetherapeutic administration for the treatment of a psychotic disorder ina patient receiving therapeutic administration of compounds of formula(I).

In a further aspect, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration ofcompounds of formula (I) in combination with at least one antipsychoticagent. The invention further provides the use of a combination ofcompounds of formula (I) and at least one antipsychotic agent in themanufacture of a medicament for simultaneous therapeutic administrationin the treatment of a psychotic disorder. The invention further providesa combination of compounds of formula (I) and at least one antipsychoticagent for simultaneous therapeutic administration in the treatment of apsychotic disorder. The invention further provides the use of compoundsof formula (I) in the manufacture of a medicament for simultaneoustherapeutic administration with at least one antipsychotic agent in thetreatment of a psychotic disorder. The invention further providescompounds of formula (I) for use for simultaneous therapeuticadministration with at least one antipsychotic agent in the treatment ofa psychotic disorder. The invention further provides the use of at leastone antipsychotic agent in the manufacture of a medicament forsimultaneous therapeutic administration with compounds of formula (I) inthe treatment of a psychotic disorder. The invention further provides atleast one antipsychotic agent for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of apsychotic disorder.

In further aspects, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration of apharmaceutical composition comprising compounds of formula (I) and atleast one mood stabilising or antimanic agent, a pharmaceuticalcomposition comprising compounds of formula (I) and at least one moodstabilising or antimanic agent, the use of a pharmaceutical compositioncomprising compounds of formula (I) and at least one mood stabilising orantimanic agent in the manufacture of a medicament for the treatment ofa psychotic disorder, and a pharmaceutical composition comprisingcompounds of formula (I) and at least one mood stabilising or antimanicagent for use in the treatment of a psychotic disorder.

Antipsychotic agents include both typical and atypical antipsychoticdrugs. Examples of antipsychotic drugs that are useful in the presentinvention include, but are not limited to: butyrophenones, such ashaloperidol, pimozide, and droperidol; phenothiazines, such aschlorpromazine, thioridazine, mesoridazine, trifluoperazine,perphenazine, fluphenazine, thiflupromazine, prochlorperazine, andacetophenazine; thioxanthenes, such as thiothixene and chlorprothixene;thienobenzodiazepines; dibenzodiazepines; benzisoxazoles;dibenzothiazepines; imidazolidinones; benziso-thiazolyl-piperazines;triazine such as lamotrigine; dibenzoxazepines, such as loxapine;dihydroindolones, such as molindone; aripiprazole; and derivativesthereof that have antipsychotic activity.

Examples of tradenames and suppliers of selected antipsychotic drugs areas follows: clozapine (available under the tradename CLOZARIL®, fromMylan, Zenith Goldline, UDL, Novartis); olanzapine (available under thetradename ZYPREX®, from Lilly); ziprasidone (available under thetradename GEODON®, from Pfizer); risperidone (available under thetradename RISPERDAL®, from Janssen); quetiapine fumarate (availableunder the tradename SEROQUEL®, from AstraZeneca); haloperidol (availableunder the tradename HALDOL®, from Ortho-McNeil); chlorpromazine(available under the tradename THORAZINE®, from SmithKline Beecham(GSK)); fluphenazine (available under the tradename PROLIXIN®, fromApothecon, Copley, Schering, Teva, and American Pharmaceutical Partners,Pasadena); thiothixene (available under the tradename NAVANE®, fromPfizer); trifluoperazine(10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazinedihydrochloride, available under the tradename STELAZINE®, from SmithKlein Beckman); perphenazine (available under the tradename TRILAFON®;from Schering); thioridazine (available under the tradename MELLARIL®;from Novartis, Roxane, HiTech, Teva, and Alpharma); molindone (availableunder the tradename MOBAN®, from Endo); and loxapine (available underthe tradename LOXITANE (D; from Watson). Furthermore, benperidol(Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®) may be used.Other antipsychotic drugs include promazine (available under thetradename SPARINE®), triflurpromazine (available under the tradenameVESPRI N®), chlorprothixene (available under the tradename TARACTAN®),droperidol (available under the tradename INAPSINE®), acetophenazine(available under the tradename TINDAL®), prochlorperazine (availableunder the tradename COMPAZINE®), methotrimeprazine (available under thetradename NOZINAN®), pipotiazine (available under the tradenamePIPOTRIL®), ziprasidone, and hoperidone.

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by adjunctivetherapeutic administration of compounds of formula (I) to a patientreceiving therapeutic administration of at least one agent suitable forthe treatment of a neurodegenerative disorder such as Alzheimer Disease.In a further aspect, the invention provides the use of compounds offormula (I) in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides compounds of formula (I) for use for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease.

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by adjunctivetherapeutic administration of at least one agent suitable for thetreatment of a neurodegenerative disorder such as Alzheimer Disease to apatient receiving therapeutic administration of compounds of formula(I). In a further aspect, the invention provides the use of at least oneagent suitable for the treatment of a neurodegenerative disorder such asAlzheimer Disease in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of compounds of formula (I). The invention furtherprovides at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of compounds of formula (I).

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by simultaneoustherapeutic administration of compounds of formula (I) in combinationwith at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides the use of a combination of compounds of formula (I)and at least one agent suitable for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in the manufacture of a medicamentfor simultaneous therapeutic administration in the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides a combination of compounds of formula (I) and at leastone agent suitable for the treatment of a neurodegenerative disordersuch as Alzheimer Disease for simultaneous therapeutic administration inthe treatment of a neurodegenerative disorder such as Alzheimer Disease.The invention further provides the use of compounds of formula (I) inthe manufacture of a medicament for simultaneous therapeuticadministration with at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease in the treatment ofa neurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides compounds of formula (I) for use for simultaneoustherapeutic administration with at least one agent suitable for thetreatment of a neurodegenerative disorder such as Alzheimer Disease inthe treatment of a neurodegenerative disorder such as Alzheimer Disease.The invention further provides the use of at least one agent suitablefor the treatment of a neurodegenerative disorder such as AlzheimerDisease in the manufacture of a medicament for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease for simultaneoustherapeutic administration with compounds of formula (I) in thetreatment of a neurodegenerative disorder such as Alzheimer Disease.

Examples of agents suitable for the treatment of a neurodegenerativedisorder such as Alzheimer Disease that are useful in the presentinvention include, but are not limited to: cholinesterase inhibitors,agents targeting nicotinic or muscarinic acethylcholine receptors, NMDAreceptors, amyloid formation, mitochondrial dysfunctions, diseaseassociated calpain activity, neuroinflamation, tumor necrosis factorreceptors, NF-kappaB, peroxisome proliferator activator receptor gamma,Apolipoprotein E variant 4 (ApoE4), disease-associated increase of theHPA axis, epileptic discharges, vascular dysfunction, vascular riskfactors, and oxidative stress.

Suitable cholinesterase inhibitors which may be used in combination withthe compounds of the inventions include for example tacrine, donepezil,galantamine and rivastigmine.

Suitable NMDA receptors targeting agents which may be used incombination with the compounds of the inventions include for examplememantine.

Suitable agents affecting increased HPA axis activity which may be usedin combination with the compounds of the inventions include for exampleCRF1 antagonists or V1b antagonists.

In a further aspect therefore, the invention provides a method oftreatment of pain by adjunctive therapeutic administration of compoundsof formula (I) to a patient receiving therapeutic administration of atleast one agent suitable for the treatment of pain. In a further aspect,the invention provides the use of compounds of formula (I) in themanufacture of a medicament for adjunctive therapeutic administrationfor the treatment of pain in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of pain.The invention further provides compounds of formula (I) for use foradjunctive therapeutic administration for the treatment of pain in apatient receiving therapeutic administration of at least one agentsuitable for the treatment of pain.

In a further aspect, the invention provides a method of treatment ofpain by adjunctive therapeutic administration of at least one agentsuitable for the treatment of pain to a patient receiving therapeuticadministration of compounds of formula (I). In a further aspect, theinvention provides the use of at least one agent suitable for thetreatment of pain in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of pain in a patientreceiving therapeutic administration of compounds of formula (I). Theinvention further provides at least one agent suitable for the treatmentof pain for adjunctive therapeutic administration for the treatment ofpain in a patient receiving therapeutic administration of compounds offormula (I).

In a further aspect, the invention provides a method of treatment ofpain by simultaneous therapeutic administration of compounds of formula(I) in combination with at least one agent suitable for the treatment ofpain. The invention further provides the use of a combination ofcompounds of formula (I) and at least one agent suitable for thetreatment of pain in the manufacture of a medicament for simultaneoustherapeutic administration in the treatment of pain. The inventionfurther provides a combination of compounds of formula (I) and at leastone agent suitable for the treatment of pain for simultaneoustherapeutic administration in the treatment of pain. The inventionfurther provides the use of compounds of formula (I) in the manufactureof a medicament for simultaneous therapeutic administration with atleast one agent suitable for the treatment of pain in the treatment ofpain. The invention further provides compounds of formula (I) for usefor simultaneous therapeutic administration with at least one agentsuitable for the treatment of pain in the treatment of pain. Theinvention further provides the use of at least one agent suitable forthe treatment of pain in the manufacture of a medicament forsimultaneous therapeutic administration with compounds of formula (I) inthe treatment of pain. The invention further provides at least one agentsuitable for the treatment of pain for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of pain.

Examples of agents suitable for the treatment of pain that are useful inthe present invention include, but are not limited to: NSAIDs(Nonsteroidal Antiinflammatory Drugs), anti-convulsant drugs such ascarbamazepine and gabapentin, sodium channel blockers, anti-depressantdrugs, cannabinoids and local anaesthetics.

Suitable agents used in combination with the compounds of the inventionsinclude for example celecoxib, etoricoxib, lumiracoxib, paracetamol,tramadol, methadone, venlafaxine, imipramine, duloxetine, bupropion,gabapentin, pregabalin, lamotrigine, fentanyl, parecoxib, nefopam,remifentanil, pethidine, diclofenac, rofecoxib, nalbuphine, sufentanil,pethidine, diamorphine and butorphanol.

It will be appreciated by those skilled in the art that the compoundsaccording to the invention may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, antidepressantagents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists,selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptakeinhibitors (SNRI), tricyclic antidepressants, dopaminergicantidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists,5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsantagents, as well as cognitive enhancers.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRIs which may be used in combination with the compounds ofthe invention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds ofthe invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of thecompounds of the invention include for example divalproex, carbamazepineand diazepam.

The following examples serve to explain the invention without limitingit.

The compounds were characterized by mass spectrometry, generallyrecorded via HPLC-MS in a fast gradient on C18-material(electrospray-ionisation (ESI) mode).

Preparation Examples

All final compounds have cis configuration at the tetrahydronaphthalencore if not otherwise noted.

Example 1[7-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3,4-dichloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester 1.11-(3,4-Dichlorobenzyl)-7-methoxy-3,4-dihydronaphthalen-2(1H)-one

15 g (85 mmol) of 7-methoxy-3,4-dihydronaphthalen-2(1H)-one weredissolved in 200 ml of dry MeOH under nitrogen. Then 6.66 g (94 mmol) ofpyrrolidine were added dropwise and slowly and the colour changes. Themixture is stirred for one h. The solvent was reduced under vacuo andthe residue was dissolved in MeCN. At 5° C. 22.5 g (94 mmol)4-(bromomethyl)-1,2-dichlorobenzene dissolved in MeCN were added and themixture was stirred over night at RT. The solvent was reduced undervacuo and the residue was mixed with MeOH/CH₂Cl₂/H₂O 1:1:1 (50 ml, 50ml, 50 ml) and 10 ml of glacial acid were added. The mixture was stirredover night. Work-up: The reaction mixture was put on ice water andextracted 3× with CH₂Cl₂. The combined organic layers were washed 1×with NaHCO₃ solution and 1× with saturated NaCl solution. The organicphase was dried on MgSO₄ and the solvent was evaporated. The residue(31.5 g) was purified by flash-chromatography on silica gel withheptane/EtOAc 2:1. 24.1 g (71.7 mmol, 84%) of the product were obtained.

ESI-MS [M+H⁺]=335.1 Calculated for C₁₈H₁₆Cl₂O₂=334.05.

1.21-(3,4-Dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-aminehydrochloride

To 1-(3,4-dichlorobenzyl)-7-methoxy-3,4-dihydronaphthalen-2(1H)-one 5.2g (15.5 mmol) in MeOH reactant ammonium acetate (12.0 g, 155 mmol) andsodium cyanoborohydride (1.46 g, 23.3 mmol) were added under nitrogen.The mixture was stirred for 4 d at RT. The solvent was reduced undervacuo and extracted with EtOAc after addition of water. The organiclayer was washed with NaCl, dried on MgSO₄ and the solvent was removed.The residue was dissolved in iPrOH and HCl in iPrOH (6N) was added.After crystallization over night the HCl-salt was separated from themother liquor and transferred to the free base with NaOH (1N). An oilwas obtained that after treatment with HCl gave the cis product (1.95 g,5.80 mmol, 37.4%) after crystallization. The mother liquor contained acis/trans mixture of the product.

ESI-MS [M+H⁺]=336.2 Calculated for C₁₈H₁₉Cl₂NO=336.26.

1.3 Ethyl1-(3,4-dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate

To 1-(3,4-dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-aminehydrochloride (1.95 g, 5.80 mmol) in pyridine 10 ml) theethylchloroformate (1.00 g, 9.28 mmol) was added slowly under nitrogen.The mixture was stirred over night at RT. The solvent was reduced undervacuo and extracted with CH₂Cl₂ after addition of HCl (1N). The organiclayer was washed with HCl (1N), NaHCO₃ solution, and NaCl solution, thendried on MgSO₄ and the solvent was removed. The product was obtained asan orange oil that precipitates after a few hours (2.10 g, 5.14 mmol,89%).

ESI-MS [M+H⁺]=408.2 Calculated for C₂₁H₂₃ClN₂O₃=407.11.

1.4 Ethyl1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate

Ethyl1-(3,4-dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(2.1 g, 5.14 mmol) was dissolved in CH₂Cl₂ (50 ml) and BBr₃ (3.87 g,15.4 mmol) was added at −10° C. The reaction mixture was slowly warmedto RT and stirred for 2 h. The reaction mixture was added to ice waterand extracted with CH₂Cl₂. The organic layer was washed with NaHCO₃solution and NaCl solution, then dried on MgSO₄ and the solvent wasremoved. The product was obtained as a brown oil (2.05 g, 5.14 mmol,100%).

ESI-MS [M+H⁺]=394.1 Calculated for C₂₀H₂₁Cl₂NO₃=393.09.

1.57-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3,4-dichloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester

NaH (55% in paraffin, 34.5 mmol) was suspended in DMA (80 ml) and ethyl1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(6.80 g, 17.3 mmol) dissolved in DMA (40 ml) was added. The mixture wasstirred for another h. Then the bromide was added in portions and themixture was stirred for 3 d at RT. The reaction mixture was added tohalf concentrated NaCl and extracted with EtOAc. The organic layer waswashed with H₂O, NaCl solution, then dried on MgSO₄ and the solvent wasremoved. Some DMA was removed on an oil pump. The residue was purifiedby flash chromatography using silica gel and CH₂Cl₂/MeOH 98:2. Theproduct was obtained as an yellow oil (9.27 g, 17.3 mmol, 100%) thatbecomes solid after a few hours.

ESI-MS [M+H⁺]=481.1 Calculated for C₂₇H₃₄Cl₂N₂O₅=536.18

Example 2 Ethyl1-(3,4-dichlorobenzyl)-7-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate2.1 Ethyl7-(2-aminoethoxy)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamatehydrochloride

[7-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3,4-dichloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester (9.27 g, 17.3 mmol) example 1 was dissolved in CH₂Cl₂(200 ml) and HCl in iPrOH (6N) was added. The reaction was stirred at RTover night after which a solid precipitates. To the reaction mixturediethyl ether was added and the precipitating HCl salt was separated byfiltration to give the final product as a solid (5.85 g, 12.3 mmol,72%).

ESI-MS [M+H⁺]=437.1 Calculated for C₂₂H₂₆Cl₂N₂O₃=436.13

2.2 Ethyl1-(3,4-dichlorobenzyl)-7-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate

Ethyl7-(2-aminoethoxy)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamatehydrochloride (100 mg, 0.229 mmol) and DMAP (27.9 mg, 0.229 mmol) weredissolved in CH₂Cl₂ (15 ml) and 1-methyl-1H-imidazole-4-sulfonylchloride (41.3 mg, 0.229 mmol) dissolved in CH₂Cl₂ (15 ml) was added.The reaction mixture was stirred over night at RT. After addition of H₂Othe phases were separated and the aqueous phase was extracted withCH₂Cl₂. The organic layer was washed with HCl (1N), NaHCO₃ solution andNaCl solution, then dried on MgSO₄ and the solvent was removed. To theresidue EtOAc/diethylether (1:1) was added, stirred, and the precipitatewas separated by filtration to obtain a brown solid of product (100 mg).

ESI-MS [M+H⁺]=581.5 Calculated for C₂₆H₃₀Cl₂N₄O₅S=580.13

Example 3N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

Ethyl1-(3,4-dichlorobenzyl)-7-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(1.00 g, 1.72 mmol) example 2 was refluxed in 25 g of EtOH/20% KOH for 2h. To the reaction mixture half concentrated NaCl solution was added andthe mixture was extracted with ethyl acetate. The organic layers werecombined and washed with NaCl solution, then dried on MgSO₄ and thesolvent was removed. A significant amount was found to be bound on MgSO₄and so additional separation/extraction with H₂O/CH₂Cl₂ and drying onNa₂SO₄ resulted in a yellow oil (830 mg). This residue was dissolved inlittle MeOH, HCl (1N) was added, and the final product (650 mg, 1.19mmol, 69%) was separated by filtration.

ESI-MS [M+H⁺]=509.1 Calculated for C₂₃H₂₆Cl₂N₄O₃S=508.11

Example 4 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

1-Methyl-1H-pyrazole-4-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrodrochloride was prepared analogously to example 3 using1-methyl-1H-pyrazole-4-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=509.1 Calculated for C₂₃H₂₆Cl₂N₄O₃S=508.11

Example 5 Pyridine-3-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Pyridine-3-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared analogously to example 3 usingpyridyl-3-sulfonyl chloride in place of 1-methyl-1H-imidazole-4-sulfonylchloride.

ESI-MS [M+H⁺]=506.1 Calculated for C₂₄H₂₅Cl₂N₃O₃S=505

Example 6

N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)propane-1-sulfonamide(example 8) (66.0 mg, 0.140 mmol), paraformaldehyde (7.63 mg, 0.254mmol), and formic acid (21.6 mg, 0.469 mmol) were dissolved in ethanol(5 ml) and refluxed for 4 h. The solvent was reduced and to the residueNaOH (1N) was added. After extraction with CH₂Cl₂ the organic layerswere washed with water and saturated NaCl solution, dried with Na₂SO₄,filtered, and the solvent was removed. The residue was purified bycolumn chromatography (CH₂Cl₂/MeOH 97:7->95:5). The final product (15.0mg, 0.028 mmol, 20%) was obtained as a brown, solid HCl salt fromisopropanol treated with HCl in isopropanol (6N).

ESI-MS [M+H⁺]=499.1 Calculated for C₂₄H₃₂Cl₂N₂O₃S=498

Example 71-(3,4-Dichloro-benzyl)-7-[2-(propane-1-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamic acid ethyl ester

{1-(3,4-Dichloro-benzyl)-7-[2-(propane-1-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester was prepared analogously to example 3 usingpropane-1-sulfonyl chloride in place of 1-methyl-1H-imidazole-4-sulfonylchloride.

ESI-MS [M+H⁺]=543.2 Calculated for C₂₅H₃₂Cl₂N₂O₅S=542

Example 8 Propane-1-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Propane-1-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared analogously to example 3 usingpropane-1-sulfonyl chloride in place of 1-methyl-1H-imidazole-4-sulfonylchloride.

ESI-MS [M+H⁺]=471.1 Calculated for C₂₂H₂₈Cl₂N₂O₃S=470

Example 9{1-(3,4-Dichloro-benzyl)-7-[2-(1-methyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

{1-(3,4-Dichloro-benzyl)-7-[2-(1-methyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester was prepared analogously to example example 3 using1-methyl-1H-pyrazole-4-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=581.2 Calculated for C₂₆H₃₀Cl₂N₄O₅S=580

Example 10{1-(3,4-Dichloro-benzyl)-7-[2-(pyridine-3-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester

{1-(3,4-Dichloro-benzyl)-7-[2-(pyridine-3-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester was prepared analogously to example 3 usingpyridine-3-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=578.2 Calculated for C₂₇H₂₉Cl₂N₃O₅S=577

Example 11N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-N-methylpropane-1-sulfonamidehydrochloride 11.1N-(1-(3,4-Dichlorobenzyl)-7-(2-(propylsulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2-trifluoroacetamide

N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)propane-1-sulfonamide(example 3, 150 mg, 0.318 mmol) and triethylamine (32.2 mg, 0.318 mmol)were dissolved in THF (10 ml) and trifluoro acetic anhydride (66.8 mg,0.318 mmol) was added. The mixture was stirred at RT for 48 h. Ethylacetate was added and the mixture was extracted with water and thenwashed with a NaHCO₃ solution and a saturated NaCl solution. Afterdrying with MgSO₄ and removal of the solvent the residue was purified bychromatography on silica gel using CH₂Cl₂/MeOH 98:2 to give the finalproduct as a colourless oil that becomes solid after a while (80.0 mg,0.141 mmol, 44%).

11.2N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-N-methylpropane-1-sulfonamidehydrochloride

NaH (3.38 mg, 0.078 mmol, 55% in oil) was suspended in DMA (5 ml) andN-(1-(3,4-dichlorobenzyl)-7-(2-(propylsulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2-trifluoroacetamide(40 mg, 0.07 mmol) dissolved in DMA (4 ml) was added dropwise. Afterstirring for 1 h iodomethane (10.5 mg, 0.074 mmol) dissolved in DMA (1ml) was added. After stirring for another 14 h the reaction mixture wasadded to a halfconcentrated solution of NaCl. Extraction with ethylacetate, washing of the organic layers with water and saturated NaClsolution followed by drying with Na₂SO₄ gave a residue that was washedwith diisopropyl ether. Cleavage of the amide bond was achieved bystirring the residue with concentrated NaOH in water and subsequentextraction with ethyl acetate. The organic layer was dried with MgSO₄and evaporated. The residue was purified by preparative HPLC (RP-18,acetonitrile/water, 0.01% TFA). After transferring the product into theHCl salt a yellow solid (11.0 mg, 0.021 mmol, 30%) was obtained.

ESI-MS [M+H⁺]=485.2 Calculated for C₂₃H₃₀Cl₂N₂O₃S=484

Example 12[1-(3,4-Dichloro-benzyl)-7-(2-methanesulfonylamino-ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester

[1-(3,4-Dichloro-benzyl)-7-(2-methanesulfonylamino-ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester was prepared analogously to example 3 using methylsulfonyl chloride in place of 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=515.1 Calculated for C₂₃H₂₈Cl₂N₂O₅S=514

Example 13[7-(2-Benzenesulfonylamino-ethoxy)-1-(3,4-dichloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester

[7-(2-Benzenesulfonylamino-ethoxy)-1-(3,4-dichloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester was prepared analogously to example 3 using phenylsulfonyl chloride in place of 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=577.2 Calculated for C₂₈H₃₀Cl₂N₂O₅S=576

Example 14{1-(3,4-Dichloro-benzyl)-7-[2-(thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester

{1-(3,4-Dichloro-benzyl)-7-[2-(thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester was prepared analogously to example 3 using phenylsulfonyl chloride in place of 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=583.1 Calculated for C₂₆H₂₈Cl₂N₂O₅S₂=582

Example 15N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-methanesulfonamidehydrochloride

N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-methanesulfonamidewas prepared analogously to example 3 using methyl sulfonyl chloride inplace of 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=443.1 Calculated for C₂₀H₂₄Cl₂N₂O₃S=442

Example 16N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-benzenesulfonamidehydrochloride

N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-benzenesulfonamidewas prepared analogously to example 3 using phenyl sulfonyl chloride inplace of 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=505.1 Calculated for C₂₅H₂₆Cl₂N₂O₃S=504

Example 17 Thiophene-2-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Thiophene-2-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidewas prepared analogously to example 3 using thiophene sulfonyl chloridein place of 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=511.1 Calculated for C₂₃H₂₄Cl₂N₂O₃S₂=510

Example 18N-{1-(3,4-Dichloro-benzyl)-7-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-2,2,2-trifluoro-acetamide

N-{1-(3,4-Dichloro-benzyl)-7-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-2,2,2-trifluoro-acetamidewas prepared analogously to example 11 using the product of example 3 inplace of example 8.

ESI-MS [M+H⁺]=605.1 Calculated for C₂₉H₂₉Cl₂F₃N₄O₄S=604

Example 19 Pyrrolidine-3-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Pyrrolidine-3-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared analogously to example 3 using benzyl3-(chlorosulfonyl)pyrrolidine-1-carboxylate (synthesis described inWO2008075070) in place of 1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=498.2 Calculated for C₂₃H₂₉Cl₂N₃O₃S=497

Example 20 1-Methyl-1H-imidazole-4-sulfonic acid{2-[8-(3,4-dichloro-benzyl)-7-formylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amide

Ethyl1-(3,4-dichlorobenzyl)-7-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(example 3, 60.0 mg, 0.103 mmol) was dissolved in THF (5 ml) and LiAlH₄(7.83 mg, 0.206 mmol) was added at RT. The residue was added to 2N NaOHand extracted with dichloromethane. The organic layer was washed withsaturated NaHCO₃ solution and then with saturated NaCl solution, driedand evaporated. The product was precipitated as an HCl salt from 6N HClin isopropanol and isopropylether to obtain the product as a white salt(36 mg, 61%).

ESI-MS [M+H⁺]=537.1 Calculated for C₂₄H₂₆Cl₂N₄O₄S=536

Example 211-(3,4-Dichloro-benzyl)-7-[2-(4-methyl-thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

1-(3,4-Dichloro-benzyl)-7-[2-(4-methyl-thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester was prepared analogously to example 3 using4-methylthiophene-2-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=597.1 Calculated for C₂₇H₃₀Cl₂N₂O₅S₂=596

Example 22{1-(3,4-Dichloro-benzyl)-7-[2-(3-fluoro-propane-1-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

{1-(3,4-Dichloro-benzyl)-7-[2-(3-fluoro-propane-1-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester was prepared analogously to example 3 using3-fluoropropane-1-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=561.2 Calculated for C₂₅H₃₁Cl₂FN₂O₅S=560

Example 23 1-Methyl-1H-imidazole-4-sulfonic acid{2-[8-(3,4-dichloro-benzyl)-7-ethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amide

Ethyl1-(3,4-dichlorobenzyl)-7-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(example 3, 60.0 mg, 0.103 mmol) was dissolved in dichloromethane (5 ml)and acetaldehyde (5.45 mg, 0.124 mmol μl) and molsieve 3{acute over (Å)}were added and the mixture was stirred for 3 h. Acetic acid (7.07 mg,0.118 mmol) was added and the mixture was stirred for another 3 h. MeOH(5 ml) and sodium cyanoborohydride (14.8 mg, 0.236 mmol) were added andit was stirred for another 14 h. Water was added and it was extractedwith dichloromethane. The organic layer was washed with saturated NaHCO₃solution, washed and evaporated. The residue was purified by columnchromatography using SiO₂ and CH₂Cl₂/MeOH 95:5->90:10. The product wasprecipitated as an HCl salt from 6N HCl in isopropanol andisopropylether to obtain the product as a white salt (17 mg, 25%).

ESI-MS [M+H⁺]=537.2 Calculated for C₂₅H₃₀Cl₂N₄O₃S=536

Example 24 4-Methyl-thiophene-2-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

4-Methyl-thiophene-2-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared analogously to example 3 using4-methylthiophene-2-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=525.1 Calculated for C₂₄H₂₆Cl₂N₂O₃S₂=524

Example 25N′-(2-{[7-amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-N,N-dimethylsulfuricdiamide hydrochloride

N′-(2-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-N,N-dimethylsulfuricdiamide hydrochloride was prepared analogously to example 3 usingdimethylsulfamoyl chloride in place of 1-methyl-1H-imidazole-4-sulfonylchloride.

ESI-MS [M+H⁺]=472.1 Calculated for C₂₁H₂₇Cl₂N₃O₃S=471

Example 26{1-(3,4-Dichloro-benzyl)-7-[2-(3,3,3-trifluoro-propane-1-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

{1-(3,4-Dichloro-benzyl)-7-[2-(3,3,3-trifluoro-propane-1-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester was prepared analogously to example 3 usingdimethylsulfamoyl chloride in place of 1-methyl-1H-imidazole-4-sulfonylchloride.

ESI-MS [M+H⁺]=597.1 Calculated for C₂₅H₂₉Cl₂F₃N₂O₅S=596

Example 27 1-Methyl-1H-imidazole-4-sulfonic acid{2-[7-amino-8-(4-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

1-Methyl-1H-imidazole-4-sulfonic acid{2-[7-amino-8-(4-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared analogously to example 3 using1-methyl-1H-imidazole-4-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride and4-(bromomethyl)-1-dichlorobenzene instead of4-(bromomethyl)-1,2-dichlorobenzene.

ESI-MS [M+H⁺]=475.1 Calculated for C₂₃H₂₇ClN₄O₃S=474

Example 28 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[7-amino-8-(4-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

1-Methyl-1H-pyrazole-4-sulfonic acid{2-[7-amino-8-(4-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared analogously to example 3 using1-methyl-1H-pyrazole-4-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride and4-(bromomethyl)-1-dichlorobenzene instead of4-(bromomethyl)-1,2-dichlorobenzene.

ESI-MS [M+H⁺]=475.1 Calculated for C₂₃H₂₇ClN₄O₃S=474

Example 297-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitriletrifluoroacetate 29.18-(3,4-Dichlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate

Ethyl1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(700 mg, 1.775 mmol, cf. example 3d) and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(761 mg, 2.13 mmol) were dissolved in dichloromethane (30 mL). Thereaction mixture was cooled to 0° C. and a solution of triethylamine(0.495 mL, 3.55 mmol) in dichloromethane (5 mL) was added dropwise. Thereaction mixture was allowed to warm to room temperature and stirringwas continued over night. The solvent was evaporated in vacuo and thecrude product was purified by flash chromatography (dichloromethane,silica gel). Yield: 934 mg (100%).

ESI-MS [M+H⁺]=526 Calculated for C₂₁H₂₀Cl₂F₃NO₅S=525.

29.2 Ethyl[7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

8-(3,4-Dichlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (250 mg, 0.475 mmol), zinc cyanide (139 mg,1.187 mmol) and tetrakistriphenyl palladium (82 mg, 0.071 mmol) indimethylformamide (5 mL) were heated in the microwave at 120° C. (100 W)under stirring for 35 min. The solvent was evaporated in vacuo and thecrude product was partitioned between ethyl acetate (40 mL) and water(30 mL). The aqueous layer was extracted with ethyl acetate one moretime (20 mL) and the combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The crude product (460 mg) was purified by flashchromatography (dichloromethane to dichloromethane:methanol=100:1,silica gel). Yield: 109 mg (0.270 mmo, 57%, colorless solid).

ESI-MS [M+H⁺]=403 Calculated for C₂₁H₂₀Cl₂N₂O₂=402.

29.37-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitriletrifluoroacetate

Ethyl[7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(50 mg, 0.124 mmol) was dissolved in 10% potassium hydroxide in ethanol(1.5 mL) and the reaction mixture was stirred at 80° C. for 2.5 h. Thesolvent was evaporated in vacuo. To the crude product brine (5 mL) and2N hydrochloric acid were added until pH 7 was reached. The aqueouslayer was extracted with dichloromethane three times. The combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Thecrude product (60 mg) was purified by preparative HPLC (xTerra prep MSC18 column, 19×150 mm, 5 μm; gradient: water, acetonitrile with 0.1%trifluoroacetic acid, flow: 20 mL/min). Yield: 6 mg (0.013 mmol, 11%).

ESI-MS [M+H⁺]=331 Calculated for C₁₈H₁₆Cl₂N₂=330.

Example 307-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrilehydrochloride 30.17-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-ol

1-(4-chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine (13.18g, 43.7 mmol, prepared analogously to1-(3,4-dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-aminecf. example 3) was dissolved in dichloromethane (200 mL). The solutionwas cooled to −10° C. and a 1 M solution of borontribromide indichloromethane (131 mL, 131 mmol) was slowly added. The reactionmixture was allowed to warm to room temperature and stirring wascontinued for 2 h. The reaction mixture was poured on ice water andsodium hydroxide was added until pH 8 was reached. The aqueous layer wasextracted with dichloromethane. The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo. The crude product was used for thenext step without further purification. Yield: 8.89 g (30.9 mmol, 71%,colorless solid).

ESI-MS [M+H⁺]=288 Calculated for C₁₇H₁₈ClNO=287.

30.2 Tert-butyl[1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2.0 g,6.95 mmol) was dissolved in dry tetrahydrofurane and di-tertiar butylcarbonate (1.517 g, 6.95 mmol) and triethylamine (2.91 mL, 20.85 mmol)were added. The reaction mixture was stirred at room temperature for 3h. The solvent was evaporated in vacuo. Water was added and the aqueouslayer was extracted with dichloromethane. The combined organic extractswere dried (Na₂SO₄) and concentrated in vacuo. The crude product wasrecrystallized from n-hexane. Yield: 2.2 g (5.67 mmol, 82%).

ESI-MS [M-isobutene+H⁺]=332 Calculated for C₂₂H₂₆ClNO₃=387.

30.37-[(Tert-butoxycarbonyl)amino]-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate

Tert-butyl[1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(850 mg, 2.191 mmol) and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(939 mg, 2.63 mmol) were dissolved in dichloromethane (45 mL). The paleyellow solution was cooled to 0° C. and a solution of triethylamine(0.611 mL, 4.38 mmol) in dichloromethane (5 mL) was added dropwise. Thereaction mixture was allowed to warm to room temperature and stirringwas continued over night. The solvent was evaporated in vacuo and thecrude product was purified by flash chromatography (dichloromethane,silica gel). Yield: 1.03 g (1.981 mmol, 90%, colorless solid).

ESI-MS [M-isobutene+CH₃CN+H⁺]=505 Calculated for C₂₃H₂₅ClF₃NO₅S=519.

30.4 Tert-butyl[1-(4-chlorobenzyl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

DPPF (8.1 mg, 0.015 mmol) and Pd₂dba₃ (3.35 mg, 0.00365 mmol) weresuspended in dimethylformamide (0.4 mL) and after stirring at roomtemperature under an inert atmosphere of nitrogen for 20 min7-[(tert-butoxycarbonyl)amino]-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (38 mg, 0.073 mmol) and zinc cyanide (12.87mg, 0.110 mmol) were added. The reaction mixture was stirred at 90° C.for 1 h. The solvent was evaporated in vacuo. Water (10 mL) was added tothe crude product and the aqueous layer was extracted with ethyl acetate(two times with 10 mL). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo. The crude product was purified byflash chromatography (dichloromethane, silica gel). Yield: 16 mg (0.040mmol, 55%).

ESI-MS [M-isobutene+CH₃CN+H⁺]=382 Calculated for C₂₃H₂₅ClN₂O₂=396.

30.57-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrilehydrochloride

Tert-butyl[1-(4-chlorobenzyl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(15 mg, 0.038 mmol) was dissolved in dichloromethane (1.5 mL) and 5 Mhydrochloric acid in isopropanol (0.3 mL) was added. The reactionmixture was stirred for 3 h at room temperature. The solvent and theexcess hydrochloric acid were evaporated in vacuo. Yield: 11 mg (0.033mmol, 87%, colorless solid).

ESI-MS [M+H⁺]=297 Calculated for C₁₈H₁₇ClN₂=296.

Example 31N-[(7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]-3-fluoropropane-1-sulfonamidetrifluoroacetate 31.1 Tert-butyl[7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

Tert-butyl[1-(4-chlorobenzyl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(52 mg, 0.131 mmol, cf. example 30d) were dissolved in methanol (5 mL).Raney nickel (about 30 mg) was added and the reaction mixture wasstirred at room temperature for 4 h under an atmosphere of hydrogen. Thecatalyst was removed by filtration. The solvent was evaporated in vacuo.The crude product was used without further purification for the nextstep. Yield: 32 mg (0.087 mmol, 67%).

ESI-MS [M-isobutene+H⁺]=311 Calculated for C₂₃H₃₀N₂O₂=366.

31.2 Tert-butyl[1-benzyl-7-({[(3-fluoropropyl)sulfonyl]amino}methyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

Tert-butyl[7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(32 mg, 0.87 mmol) was dissolved in dichloromethane (15 mL) and4-dimethylaminopyridine (12 mg, 0.096 mmol) and3-fluoropropane-1-sulfonyl chloride (14 mg, 0.087 mmol) were added. Thereaction mixture was stirred at room temperature over night. Thedichloromethane solution of the crude product was washed successivelywith 1N aqueous hydrochloric acid and aqueous NaHCO₃ solution, dried(Na₂SO₄) and concentrated in vacuo. The crude product was purified byflash chromatography (dichloromethane, methanol, silica gel). Yield: 9.3mg (0.019 mmol, 22%).

ESI-MS [M-isobutene+H⁺]=435 Calculated for C₂₆H₃₅FN₂O₄S=490.

31.3N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-3-fluoropropane-1-sulfonamidetrifluoroacetate

Tert-butyl[1-benzyl-7-({[(3-fluoropropyl)sulfonyl]amino}methyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(9.3 mg, 0.019 mmol) was dissolved in dichloromethane (10 mL) andtrifluoroacetic acid (excess) was added. The reaction mixture wasstirred at room temperature for 4 h. The solvent was evaporated in vacuoand the crude product was purified by flash chromatography (silica gel,dichloromethane, methanol). Yield: 4 mg (0.0079 mmol, 42%).

ESI-MS [M+H⁺]=391 Calculated for C₂₁H₂₇FN₂O₂S=390.

Example 32 Ethyl[7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

Cf. Example 29b.

ESI-MS [M+H⁺]=403 Calculated for C₂₁H₂₀Cl₂N₂O₂=402.

Example 331-(3-chlorobenzyl)-7-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]-1,2,3,4-tetrahydronaphthalen-2-aminehydrochloride

ESI-MS [M+H⁺]=435 Calculated for C₂₂H₂₇ClN₂O₃S=434.

Example 34 tert-Butyl[7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate34.1 7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-ol

1-(3,4-Dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine(10 g, 26.8 mmol, cf. example 3.2 were dissolved in dichloromethane (240mL). The suspension was cooled to −10° C. and a 1 M solution ofbortribromide in dichloromethane (80 mL, 80 mmol). The solution wasallowed to warm to room temperature and stirring was continued for 3 h.The reaction mixture was poured on ice (1 L). The aqueous layer was madealkaline (pH 10) with 2N sodium hydroxide solution. The layers wereseparated. The aqueous layer was extracted with dichloromethane and thecombined organic layers were washed with saturated NaHCO₃ solution andwater. The organic layers were dried (Na₂SO₄) and concentrated in vacuo.The crude product was used without further purification for the nextstep. Yield: 10.8 g

ESI-MS [M+H⁺]=322 Calculated for C₁₇H₁₇Cl₂NO=321.

34.2 tert-Butyl[1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-ol (10.8g) and triethylamine (14.01 mL, 101 mmol) were dissolved in drytetrahydrofuran (200 mL). Di-tert-butyl carbonate (7.31 g, 33.5 mmol)was added in small portions at room temperature. The reaction mixturewas stirred over night. The solvent was evaporated in vacuo. The residuewas dissolved in ethyl acetate (300 mL) and washed with water (2×200mL). The ethyl acetate solution of the crude product was dried (Na₂SO₄).The solvent was evaporated in vacuo and the crude product was used forthe next step without further purification. Yield: 12.2 g.

ESI-MS [M-isobutene+CH3CN+H⁺]=407 Calculated for C₂₂H₂₅Cl₂NO₃=421.

34.37-[(tert-Butoxycarbonyl)amino]-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate

tert-Butyl[1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(4.06 g, 9.66 mmol) and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(4.14 g, 11.59 mmol) were dissolved in dichloromethane (190 mL). Thelight brown solution was cooled to 0° C. and triethylamine (2.69 mL,19.32 mmol) in dichloromethane (10 mL) was added dropwise. The reactionmixture was allowed to warm to room temperature and stirring wascontinued over night. The solvent was evaporated in vacuo and the crudeproduct was purified by flash chromatography (dichloromethane, silicagel). Yield: 3.2 g (5.77 mmol, 60%).

34.4 tert-Butyl[7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

Diphenylphosphinoferrocene (100 mg, 0.18 mmol) and dipalladiumtrisdibenzylideneacetone (41 mg, 0.045 mmol) were suspended under anatmosphere of argon in dry dimethylformamide (5 mL). After stirring atroom temperature for 40 min7-[(tert-butoxycarbonyl)amino]-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (0.5 g, 0.902 mmol) was added and the reactionmixture was heated to 90° C. Over 30 min zinc cyanide (159 mg, 1.353mmol) was added in small portions. After complete addition stirring wascontinued at 90° C. for 2 h. The reaction mixture was cooled to roomtemperature diluted with dichloromethane (50 mL), washed with saturatedNaHCO₃ (3×10 mL). The organic layer was dried (MgSO₄) and concentratedin vacuo. The crude product was purified by flash chromatography(dichloromethane, silica gel). Yield: 97 mg (0.225 mmol, 25%).

ESI-MS [M+Na⁺]=453 Calculated for C₂₃H₂₄Cl₂N₂O₂=430.

Example 357-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-oltrifluoroacetate (salt)

Cf. example 34a

ESI-MS [M+H⁺]=322 Calculated for C₁₇H₁₇Cl₂NO=321.

Example 361-(4-chlorobenzyl)-7-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-2-aminehydrochloride 36.1 tert-Butyl[1-(4-chlorobenzyl)-7-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

Tert-butyl[1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(180 mg, 0.464 mmol, prepared analogously to tert-butyl[1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate,cf. Example 34.2 and potassium hydroxide (1.4 g, 25 mmol) were suspendedin acetonitrile (4 mL). After stirring the two phase system for 45 minat room temperature the reaction mixture was cooled to −15° C. and asolution of 2-chloro-2,2-difluoro-1-phenylethanone (442 mg, 2.32 mmol)in acetonitrile (1 mL) was added dropwise over 30 min. The reactionmixture was warmed to room temperature and then heated at 80° C. for 2h. The reaction mixture was cooled to room temperature and diluted withethyl acetate. The aqueous layer was extracted with ethyl acetate. Thecombined extracts were dried (MgSO₄) and concentrated in vacuo. Thecrude product was purified by flash chromatography (dichloromethane,silica gel). Yield: 30 mg (0.069 mmol, 15%).

ESI-MS [M-isobutene+CH3CN+H⁺]=423 Calculated for C₂₃H₂₆ClF₂NO₃=437.

36.21-(4-Chlorobenzyl)-7-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-2-aminehydrochloride

tert-Butyl[1-(4-chlorobenzyl)-7-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(30 mg, 0.069 mmol) was dissolved in dichloromethane (2 mL). 5Nisopropanolic hydrochloric acid (0.3 mL) were added and the reactionmixture was stirred at room temperature for 3 h. The solvents wereevaporated in vacuo. Yield: 26 mg (0.069 mmol, 100%, colorless solid).

ESI-MS [M+H⁺]=338 Calculated for C₁₈H₁₈ClF₂NO=337.

Example 37 Benzyl[1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

tert-Butyl[1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(2 g, 6.95 mmol, prepared analogously to tert-butyl[1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate,cf. example 34.2 were suspended in dimethylformamide (40 mL).Triethylamine (0.969 mL, 6.95 mmol) and benzyl carbonochloridate (1.186g, 6.95 mmol) were added. The reaction mixture was stirred at roomtemperature over night. The solvent was evaporated in vacuo. To thecrude product ethyl acetate and water were added. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were dried(MgSO₄) and concentrated in vacuo. The crude product was purified byflash chromatography (silica gel, dichloromethane, methanol). Yield: 393mg (0.931 mmol, 13.4%, colorless foam).

ESI-MS [M+H⁺]=422 Calculated for C₂₅H₂₄ClNO₃=421.

Example 38 tert-Butyl[7-(aminomethyl)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

tert-Butyl[7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(30 mg, 0.07 mmol, cf. example 34d) were dissolved in methanol (3 mL).Raney nickel (10 mg) was added and the reaction mixture stirred at roomtemperature under an atmosphere of hydrogen for 4 h. The catalyst wasremoved by filtration and the methanol was evaporated in vacuo. Yield:18 mg (0.041 mmol, 59%).

ESI-MS [M+H⁺]=435 Calculated for C₂₃H₂₈Cl₂N₂O₂=434.

Example 39 tert-Butyl[1-(3,4-dichlorobenzyl)-7-{[(propylsulfonyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

tert-Butyl[7-(aminomethyl)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(120 mg, 0.276 mmol, cf. Example 38) was dissolved in dichloromethane (5mL). 4-Dimethylaminopyridine (35 mg, 0.289 mmol) was added. Afterstirring at room temperature for 5 min propane-1-sulfonyl chloride (39mg, 0.031 mmol) was added and stirring was continued over night. Thereaction mixture was diluted with dichloromethane and washedsuccessively with 0.5 N hydrochloric acid (2×2 mL) and saturated NaHCO₃(1×2 mL). The organic phase was dried (MgSO₄) and concentrated in vacuo.The crude product was used for the next step without furtherpurification. Yield: 125 mg (0.231 mmol, 84%).

ESI-MS [M+Na⁺]=563 Calculated for C₂₆H₃₄Cl₂N₂O₄S=540.

Example 40N-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

Tert-butyl[1-(3,4-dichlorobenzyl)-7-{[(propylsulfonyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(120 mg, 0.222 mmol, cf. example 39) was dissolved in 5 N isopropanolichydrochloric acid (2 mL). The reaction mixture was stirred at roomtemperature for 1 h. The solvent was evaporated and the product wasdried in vacuo. Yield: 101 mg (0.211 mmol, 95%).

ESI-MS [M+H⁺]=441 Calculated for C₂₁H₂₆Cl₂N₂O₂S=440.

Example 41N-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-3-fluoropropane-1-sulfonamidehydrochloride

The compound was prepared analogously to example 40 using3-fluoropropane-1-sulfonyl chloride in place of n-propane-1-sulfonylchloride.

ESI-MS [M+H⁺]=459 Calculated for C₂₁H₂₅Cl₂FN₂O₂S=458.

Example 42N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidetrifluoroacetate

N-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride (40 mg, 0.084 mmol, cf. example 40) were dissolved inmethanol (4 mL) and hydrogenated at the H-cube (1 h, 40° C., 30 bar, 20%Pd/C). The solvent was evaporated and the crude product was purified bypreparative HPLC (xTerra prep MS C18 column, 19×150 mm, 5 μm; gradient:water, acetonitrile with 0.1% trifluoroacetic acid, flow: 20 mL/min).Yield: 4.9 mg (0.0102 mmol, 12%).

ESI-MS [M+H⁺]=373 Calculated for C₂₁H₂₈N₂O₂S=372.

Example 43N-{[cis-7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}cyclobutanesulfonamidehydrochloride

The compound was prepared analogously to example 40 usingcyclobutylsulfonyl chloride in place of n-propane-1-sulfonyl chloride.

ESI-MS [M+H⁺]=385 Calculated for C₂₂H₂₈N₂O₂S=384.

Example 44N-{[cis-7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-cyclopropylmethanesulfonamidehydrochloride

The compound was prepared analogously to example 40 usingcyclopropylmethanesulfonyl chloride in place of n-propane-1-sulfonylchloride.

ESI-MS [M+H⁺]=385 Calculated for C₂₂H₂₈N₂O₂S=384.

Example 45N-{[cis-7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-N-methylpropane-1-sulfonamidehydrochloride

Tert-butyl-1-benzyl-7-(propylsulfonamidomethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(35 mg, 0.074 mmol, prepared analog to example 40) was dissolved inacetonitrile (1 mL). Cesium carbonate (29 mg, 0.09 mmol)) andmethyliodide (12 μL, 0.19 mmol) were added successively and the reactionmixture was heated in the microwave to 100° C. for 3 h. The solventswere evaporated in vacuo. The residue was treated with dichloromethaneand washed with water. The organic layer was dried (MgSO₄) andconcentrated. The crude product was dissolved in isopropanol and treatedwith 5 M hydrochloric acid in isopropanol. The solvent was evaporated invacuo to yield the final product as colorless solid. Yield: 18 mg (0.043mmol, 58%).

ESI-MS [M+H⁺]=387 Calculated for C₂₂H₃₀N₂O₂S=386.

Example 46{1-(3-Chloro-benzyl)-7-[2-(1-methyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester 46.17-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester

7-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester was prepared in analogy to example 1 using1-bromomethyl-3-chloro-benzene in place of4-(bromomethyl)-1,2-dichlorobenzene.

ESI-MS [M+H⁺]=503 Calculated for C₂₇H₃₅ClN₂O₅=502

46.2{1-(3-Chloro-benzyl)-7-[2-(1-methyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

{1-(3-Chloro-benzyl)-7-[2-(1-methyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester was prepared starting from7-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester from previous step in analogy to example 2 using1-methyl-1H-pyrazole-4-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=547 Calculated for C₂₆H₃₁ClN₄O₅=546

Example 47 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

1-Methyl-1H-pyrazole-4-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared in analogy to example 3 starting from{1-(3-Chloro-benzyl)-7-[2-(1-methyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 46)

ESI-MS [M+H⁺]=475 Calculated for C₂₃H₂₇ClN₄O₃S=474

Example 48 1-Methyl-1H-imidazole-4-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

1-Methyl-1H-imidazole-4-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared in three steps from7-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 47 using1-Methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=475 Calculated for C₂₃H₂₇ClN₄O₃S=474

Example 49{1-(3-Chloro-benzyl)-7-[2-(2,4-dimethyl-thiazole-5-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using2,4-dimethyl-thiazole-5-sulfonyl chloride.

ESI-MS [M+H⁺]=578 Calculated for C₂₇H₃₂ClN₃O₅S₂=577

Example 50{1-(3-Chloro-benzyl)-7-[2-(thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using thiophene-2-sulfonylchloride.

ESI-MS [M+H⁺]=549 Calculated for C₂₆H₂₉ClN₂O₅S₂=548

Example 51{1-(3-Chloro-benzyl)-7-[2-(5-chloro-thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using5-Chloro-thiophene-2-sulfonyl chloride.

ESI-MS [M+H⁺]=583 Calculated for C₂₆H₂₈Cl₂N₂O₅S₂=582

Example 52{1-(3-Chloro-benzyl)-7-[2-(2-methyl-3H-imidazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using2-Methyl-3H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=547 Calculated for C₂₆H₃₁ClN₄O₅S=546

Example 53{1-(3-Chloro-benzyl)-7-[2-(5-methyl-thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using5-Methyl-thiophene-2-sulfonyl chloride.

ESI-MS [M+H⁺]=563 Calculated for C₂₇H₃₁ClN₂O₅S₂=562

Example 54{1-(3-Chloro-benzyl)-7-[2-(4-methyl-thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using4-Methyl-thiophene-2-sulfonyl chloride.

ESI-MS [M+H⁺]=563 Calculated for C₂₇H₃₁ClN₂O₅S₂=562

Example 55 Propane-1-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in three steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 48 using propane-1-sulfonylchloride.

ESI-MS [M+H⁺]=437 Calculated for C₂₂H₂₉ClN₂O₃S=436

Example 56 Thiophene-2-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amide

Prepared in one step from{1-(3-chloro-benzyl)-7-[2-(thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester in analogy to example 48.

ESI-MS [M+H⁺]=477 Calculated for C₂₃H₂₅ClN₂O₃S₂=476

Example 57 2,4-Dimethyl-thiazole-5-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amide

Prepared in one step from{1-(3-Chloro-benzyl)-7-[2-(2,4-dimethyl-thiazole-5-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 49) in analogy to example 48.

ESI-MS [M+H⁺]=506 Calculated for C₂₄H₂₈ClN₃O₃S₂=505

Example 58 2-Methyl-3H-imidazole-4-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amide

Prepared in one step from{1-(3-Chloro-benzyl)-7-[2-(2-methyl-3H-imidazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 52) in analogy to example 48.

ESI-MS [M+H⁺]=475 Calculated for C₂₃H₂₇ClN₄O₃S=474

Example 59 5-Chloro-thiophene-2-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amide

Prepared in one step from{1-(3-chloro-benzyl)-7-[2-(5-chloro-thiophene-2-sulfonylamino)ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 51) in analogy to example 48.

ESI-MS [M+H⁺]=511 Calculated for C₂₃H₂₄Cl₂N₂O₃S₂=510

Example 60{1-(3-Chloro-benzyl)-7-[2-(2,5-dimethyl-thiophene-3-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using2,5-Dimethyl-thiophene-3-sulfonyl chloride.

ESI-MS [M+H⁺]=577 Calculated for C₂₈H₃₃ClN₂O₅S₂=576

Example 61{1-(3-Chloro-benzyl)-7-[2-(1-ethyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using1-Ethyl-1H-pyrazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=561 Calculated for C₂₇H₃₃ClN₄O₅S=560

Example 62{1-(2,4-Dichloro-benzyl)-7-[2-(1-methyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared as described for example 46 using1-bromomethyl-2,4-dichloro-benzene in place of4-(bromomethyl)-3-chlorobenzene.

ESI-MS [M+H⁺]=581 Calculated for C₂₆H₃₀Cl₂N₄O₅S=580

Example 63{1-(2,4-Dichloro-benzyl)-7-[2-(thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester

Prepared as described for example 62 using thiophene-2-sulfonyl chloridein place of 1-methyl-1H-pyrazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=583 Calculated for C₂₆H₂₈Cl₂N₄O₅S₂=582

Example 64{1-(2,4-Dichloro-benzyl)-7-[2-(5-methyl-thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared as described for example 62 using 5-methyl-thiophene-2-sulfonylchloride in place of 1-Methyl-1H-pyrazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=597 Calculated for C₂₇H₃₀Cl₂N₂O₅S₂=596

Example 65[1-(3-Chloro-benzyl)-7-(2-ethanesulfonylamino-ethoxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using ethane-sulfonylchloride.

ESI-MS [M+H⁺]=495 Calculated for C₂₄H₃₁ClN₂O₅S=494

Example 66 1-Ethyl-1H-pyrazole-4-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in one step from{1-(3-chloro-benzyl)-7-[2-(1-ethyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 61) in analogy to example 48.

ESI-MS [M+H⁺]=489 Calculated for C₂₄H₂₉ClN₄O₃S=488

Example 67 4-Methyl-thiophene-2-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in one step from{1-(3-chloro-benzyl)-7-[2-(2-methyl-3H-imidazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 53) in analogy to example 48.

ESI-MS [M+H⁺]=491 Calculated for C₂₄H₂₇ClN₂O₃S₂=490

Example 68 5-Methyl-thiophene-2-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in one step from{1-(3-chloro-benzyl)-7-[2-(5-methyl-thiophene-2-sulfonylamino)ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 53) in analogy to example 48.

ESI-MS [M+H⁺]=491 Calculated for C₂₄H₂₇ClN₂O₃S₂=490

Example 69 2,5-Dimethyl-thiophene-3-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in one step from{1-(3-Chloro-benzyl)-7-[2-(2,5-dimethyl-thiophene-3-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 60) in analogy to example 48.

ESI-MS [M+H⁺]=505 Calculated for C₂₅H₂₉ClN₂O₃S₂=504

Example 70 Ethanesulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in one step from[1-(3-chloro-benzyl)-7-(2-ethanesulfonylamino-ethoxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester (example 65) in analogy to example 48.

ESI-MS [M+H⁺]=423 Calculated for C₂₁H₂₇ClN₂O₃S=422

Example 71 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[7-amino-8-(2,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in one step from{1-(2,4-dichloro-benzyl)-7-[2-(1-methyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 62) in analogy to example 48.

ESI-MS [M+H⁺]=509 Calculated for C₂₃H₂₆Cl₂N₄O₃S=508

Example 72 Thiophene-2-sulfonic acid{2-[7-amino-8-(2,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in one step from{1-(2,4-dichloro-benzyl)-7-[2-(thiophene-2-sulfonylamino)ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 63) in analogy to example 48.

ESI-MS [M+H⁺]=511 Calculated for C₂₃H₂₄Cl₂N₂O₃S₂=510

Example 73 5-Methyl-thiophene-2-sulfonic acid{2-[7-amino-8-(2,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in one step from{1-(2,4-dichloro-benzyl)-7-[2-(5-methyl-thiophene-2-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 64) in analogy to example 48.

ESI-MS [M+H⁺]=525 Calculated for C₂₄H₂₆Cl₂N₂O₃S₂=524

Example 74{1-(2,4-Dichloro-benzyl)-7-[2-(propane-1-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester

Prepared as described for example 62 using propane-1-sulfonyl chloridein place of 1-methyl-1H-pyrazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=543 Calculated for C₂₅H₃₂Cl₂N₂O₅S=542

Example 75 Propane-1-sulfonic acid{2-[7-amino-8-(2,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in one step from{1-(2,4-dichloro-benzyl)-7-[2-(propane-1-sulfonylamino)ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester (example 74) in analogy to example 48.

ESI-MS [M+H⁺]=471 Calculated for C₂₂H₂₈Cl₂N₂O₃S=470

Example 76(1-(4-Chloro-benzyl)-7-{(2-[methyl-(propane-1-sulfonyl)-amino]-ethoxy}-1,2,3,4-tetrahydronaphthalen-2-yl)-carbamicacid ethyl ester 76.1 2-(N-methylpropylsulfonamido)ethylpropane-1-sulfonate

To a cooled solution (0-5° C.) of 2-(methylamino)ethanol (8.56 ml, 107mmol) in 100 ml DCM was added dropwise a solution of propane-1-sulfonylchloride (13.1 ml, 117 mmol) in 50 ml DCM over an 1 h period. Theresulting mixture was stirred at room temperature over night. Water and10% citric acid were added and then was extracted with DCM, dried overMgSO₄, filtrated and evaporated to obtain a yellow/orange oil. (13.6 g)Chromatography afforded 2.75 g of product.

76.2(1-(4-Chloro-benzyl)-7-{2-[methyl-(propane-1-sulfonyl)-amino]-ethoxy}-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamicacid ethyl ester

A solution of ethyl1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(0.128 g, 0.355 mmol) in DMF under N₂ was treated with sodium hydride(0.014 g, 0.568 mmol) and the reaction was stirred for 30 minutes atroom temperature. A solution of 2-(N-methylpropylsulfonamido)ethylpropane-1-sulfonate (0.102 g, 0.355 mmol) (see step 1) in DMF was addedand the reaction mixture was stirred at ambient temperature over night.The mixture was portioned between ethyl acetate and water. The organiclayer was washed with water, dried (MgSO₄), filtrated and evaporated toafford brown/white crystals. After addition of a few drops of ethylacetate/cyclohexane (1:4) a white precipitate formed. Yield 43 mg

ESI-MS [M+H⁺]=523 Calculated for C₂₆H₃₅ClN₂O₅S=522

Example 77 Propane-1-sulfonic acid{2-[7-amino-8-(4-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-methyl-amidehydrochloride

Prepared in one step from(1-(4-chloro-benzyl)-7-{2-[methyl-(propane-1-sulfonyl)-amino]-ethoxy}-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamicacid ethyl ester (example 76) in analogy to example 48.

ESI-MS [M+H⁺]=451 Calculated for C₂₃H₃₁ClN₂O₃S=450

Example 78(1-(3-Chloro-benzyl)-7-{2-[methyl-(propane-1-sulfonyl)-amino]-ethoxy}-1,2,3,4-tetrahydronaphthalen-2-yl)-carbamicacid ethyl ester

Prepared from[1-(3-chloro-benzyl)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester as described example 77.

ESI-MS [M+H⁺]=523 Calculated for C₂₆H₃₅ClN₂O₅S=522

Example 79 Propane-1-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-methyl-amide hydrochloride

Prepared in one step from(1-(3-chloro-benzyl)-7-{2-[methyl-(propane-1-sulfonyl)-amino]-ethoxy}-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamicacid ethyl ester (example 78) in analogy to example 48.

ESI-MS [M+H⁺]=451 Calculated for C₂₃H₃₁ClN₂O₃S=450

Example 80{1-(3-Chloro-benzyl)-7-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using1-Methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=547 Calculated for C₂₆H₃₁ClN₄O₅S=546

Example 81{1-(3-Chloro-benzyl)-7-[2-(1-difluoromethyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in two steps from7-(2-tert-butoxycarbonylamino-ethoxy)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 46 using1-difluoromethyl-1H-pyrazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=583 Calculated for C₂₆H₂₉ClF₂N₄O₅S=582

Example 821-(3-Chloro-benzyl)-7-[(R)-1-(propane-1-sulfonyl)-pyrrolidin-2-ylmethoxy]-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride 82.1 (Propane-1-sulfonic acid(R)-1-(propane-1-sulfonyl)-pyrrolidin-2-ylmethyl ester

Prepared as described for 2-(N-methylpropylsulfonamido)ethylpropane-1-sulfonate (example 76, step 1 using(R)-1-pyrrolidin-2-yl-methanol instead of 2-(methylamino)ethanol.

82.21-(3-Chloro-benzyl)-7-[(R)-1-(propane-1-sulfonyl)-pyrrolidin-2-ylmethoxy]-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride

Prepared in two steps from (propane-1-sulfonic acid(R)-1-(propane-1-sulfonyl)-pyrrolidin-2-ylmethyl ester (see previousstep) and ethyl1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamateas described for example 77.

ESI-MS [M+H⁺]=477 Calculated for C₂₅H₃₃ClN₂O₃S=476

Example 831-(3-Chloro-benzyl)-7-[1-(propane-1-sulfonyl)-azetidin-3-yloxy]-1,2,3,4-tetrahydronaphthalen-2-ylaminehydrochloride 83.1 1-(Propane-1-sulfonyl)-azetidin-3-ol

To a cooled solution (0-5° C.) of azetidin-3-ol hydrochloride (1 g, 9.13mmol) in 10 ml dichloromethane containing diisopropyl ethyl amine (2,391ml, 13.69 mmol) was added dropwise a solution of propane-1-sulfonylchloride (1,126 ml, 10.04 mmol) dissolved in 5 ml dichloromethane overan 1 h period. The mixture was allowed to warm up to room temperatureand was stirred over night. Citric acid (10%) was added, extracted withdichloromethane, dried over MgSO₄, filtered and the solvent wasevaporated to obtain 597 mg of a yellow oil, which was purified bychromatography (yield 470 mg)

83.2 Methanesulfonic acid 1-(propane-1-sulfonyl)-azetidin-3-yl ester

To a solution of 1-(propane-1-sulfonyl)-azetidin-3-ol (236 mg, 1.317mmol) in pyridine was added drop wise methane sulfonyl chloride (205 μl,2.63 mmol) at 0° C. The mixture was allowed to warm up to roomtemperature and was stirred for 3 h. Dichloromethane was added. Themixture was subsequently washed with water, saturated NaHCO₃ and brine,dried (MgSO4), and filtrated. The solvent was evaporated to obtain 293mg of crude product which was used without further purification.

83.31-(3-Chloro-benzyl)-7-[1-(propane-1-sulfonyl)-azetidin-3-yloxy]-1,2,3,4-tetrahydronaphthalen-2-ylaminehydrochloride

Prepared in two steps from methanesulfonic acid1-(propane-1-sulfonyl)-azetidin-3-yl ester (see previous step) and ethyl1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamateas described for example 77.

ESI-MS [M+H⁺]=449 Calculated for C₂₃H₂₉ClN₂O₃S=448

Example 841-(3-Chloro-benzyl)-7-(3-ethanesulfonyl-propoxy)-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride

Prepared in two steps from 1-chloro-3-ethanesulfonyl-propane (see:Synthetic Communications, 19(9-10), 1583-91; 1989) and ethyl1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamatein analogy to example 77.

ESI-MS [M+H⁺]=422 Calculated for C₂₂H₂₈ClNO₃S=421

Example 85 Cyclohexanesulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Cyclohexanesulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared in analogy to example 3 usingcyclohexyl-sulfonyl chloride in place of1-methyl-1H-imidazole-4-sulfonyl chloride.

ESI-MS [M+H⁺]=511 Calculated for C₂₅H₃₂Cl₂N₂O₃S=510

Example 86 2-Trimethylsilanyl-ethanesulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

2-Trimethylsilanyl-ethanesulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidhydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=529 Calculated for C₂₄H₃₄Cl₂N₂O₃SSi=528

Example 87N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-(5-methyl-isoxazol-3-yl)-methanesulfonamidehydrochloride

N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-(5-methyl-isoxazol-3-yl)-methanesulfonamidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=524 Calculated for C₂₄H₂₇Cl₂N₃O₄S=523

Example 88 Cyclobutanesulfonic acid{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

88.11-(1-(3,4-Dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyrrolidine

1-(3,4-Dichlorobenzyl)-7-methoxy-3,4-dihydronaphthalen-2(1H)-one (5.5 g,16.4 mmol, example 1), pyrrolidine (1.40 g, 19.7 mmol), andp-toluenesulfonic acid monohydrate (31.0 mg, 0.164 mmol) were dissolvedin toluene (100 ml) and refluxed for 2 h using a Dean-Stark condenser.The solvent was removed and after addition of MeOH (50 ml) and sodiumcyanohydride (1.57 g, 24.6 mmol) the mixture was stirred for 4 d at roomtemperature under nitrogen. Water was added, the organic phase separatedand the aqueous phase extracted with ethyl acetate. The combined organiclayers were washed with saturated NaCl solution, dried over MgSO₄, andconcentrated to afford a residue that was purified by flashchromatography (silica gel, MeOH/CH₂Cl₂3:97→5:95). The beige solidproduct (1.6 g, 25%) was obtained from precipitation in ethylacetate/diisopropylether (1:1).

88.28-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol

1-(1-(3,4-Dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyrrolidine(1.6 g, 4.10 mmol) was dissolved in CH₂Cl₂ (100 ml) and BBr₃ (1 molar inCH₂Cl₂, 12.3 ml, 12.3 mmol) was added at −10° C. It was stirred for 2 hafter which time the temperature rose to room temperature. Ice water wasadded, the organic phase separated and the aqueous phase extracted withCH₂Cl₂. The combined organic layers were washed with saturated NaHCO₃and NaCl solution, dried over Na₂SO₄, and concentrated to afford aresidue. The beige solid product (1.2 g, 78%) was obtained fromprecipitation in ethyl acetate.

88.3 tert-Butyl2-(8-(3,4-dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethylcarbamate

NaH in paraffin (0.278 g, 6.38 mmol, 55% in paraffin) was washed withn-hexane and suspended in DMA (30 ml).8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol(1.2 g, 3.19 mmol) in DMA (20 ml) was added. After stirring for 1 h atroom temperature tert-butyl 2-bromoethylcarbamate (2.14 g, 6.38 mmol)was added in portions and the mixture was stirred for 48 h. Water wasadded and the aqueous phase was extracted with ethyl acetate. Thecombined organic layers were washed with saturated NaCl solution, driedover Na₂SO₄, and concentrated to afford a residue that was purified byflash chromatography (silica gel, MeOH/CH₂Cl₂3:97). The product (1.6 g,97%) was obtained as a yellow oil.

88.42-(8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethanaminehydrochloride

tert-Butyl2-(8-(3,4-dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethylcarbamate(1.6 g, 3.08 mmol) was dissolved in CH₂Cl₂ (70 ml) and HCl in iPrOH wasadded. It was stirred for 14 h at room temperature after during whichtime the temperature rose to room temperature. The solvent was removedto obtain white salt (1.2 g, 85%).

88.5 Cyclobutanesulfonic acid{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

2-(8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethanamine(120 mg, 0.286 mmol), para-(N,N-dimethylamino) pyridine (1.40 g, 19.7mmol), and cyclobutanesulfonyl chloride (46.5 mg, 0.30 mmol) weredissolved in CH₂Cl₂ (20 ml) and stirred for 14 h at room temperature.0.5N HCl was added, the organic phase separated and the aqueous phaseextracted with CH₂Cl₂. The combined organic layers were washed withwater, NaHCO₃ solution, and saturated NaCl solution, dried over Na₂SO₄,and concentrated to afford a residue that was purified by flashchromatography (silica gel, MeOH/CH₂Cl₂3:97→5:95). The white solidproduct (164 mg, 32%) was transferred to an HCl salt and precipitatedfrom diisopropyl ether.

ESI-MS [M+H⁺]=537 Calculated for C₂₇H₃₄Cl₂N₂O₃S=536

Example 89 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-methyl-amidehydrochloride

N-(2-(8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride (41 mg, 0.068 mmol, Example 91, iodomethane (11.6 mg,0.082 mmol), caesium carbonate (49.0 mg, 0.150 mmol) were dissolved inacetonitrile (3 ml) and stirred for 1 h at 100° C. in the microwave.After addition of another iodomethane (11.6 mg, 0.082 mmol) and caesiumcarbonate (49.0 mg, 0.150 mmol) it was stirred for another 1 h at 100°C. in the microwave. Water and CH₂Cl₂ were added, the organic phaseseparated and the aqueous phase extracted with CH₂Cl₂. The combinedorganic layers were washed with saturated NaCl solution, dried overNa₂SO₄, and concentrated to afford a residue that was purified by flashchromatography (silica gel, MeOH/CH₂Cl₂ 3:97→5:95). The white solidproduct (42 mg, 38%) was transferred to an HCl salt and precipitatedfrom diisopropyl ether. ESI-MS [M+H⁺]=577

Calculated for C₂₈H₃₄Cl₂N₄O₃S=576

Example 90 Butane-1-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Butane-1-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=485 Calculated for C₂₃H₃₀Cl₂N₂O₃S=484

Example 91 Propane-2-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Propane-2-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=471 Calculated for C₂₂H₂₈Cl₂N₂O₃S=470

Example 92 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

1-Methyl-1H-pyrazole-4-sulfonic acid{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared in analogy to example 88.

ESI-MS [M+H⁺]=563 Calculated for C₂₇H₃₂Cl₂N₄O₃S=562

Example 93 2-Ethoxy-ethanesulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

2-Ethoxy-ethanesulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=501 Calculated for C₂₃H₃₀Cl₂N₂O₄S=500

Example 94 Cyclobutanesulfonic acid{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-methyl-amidehydrochloride

Cyclobutanesulfonic acid{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-methyl-amidehydrochloride was prepared fromN-(2-(8-(3,4-dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)cyclobutanesulfonamidehydrochloride (example 88) in analogy to example 89.

ESI-MS [M+H⁺]=551 Calculated for C₂₈H₃₆Cl₂N₂O₃S=550

Example 95N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-methanesulfonamidehydrochloride

N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-methanesulfonamidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=483 Calculated for C₂₃H₂₈Cl₂N₂O₃S=482

Example 96 Propane-1-sulfonic acid{2-[7-amino-8-(4-methoxy-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Propane-1-sulfonic acid{2-[7-amino-8-(4-methoxy-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=433 Calculated for C₂₃H₃₂N₂O₄S=432

Example 97N-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-methanesulfonamidehydrochloride

N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)methanesulfonamidehydrochloride (50.0 mg, 0.104 mmol), Pd—C 10% (1.10 mg), and hydrazinemonohydrate (522 mg, 10.4 mmol) were suspended in ethanol (5 ml) andstirred for 4 h under reflux. Water and CH₂Cl₂ were added, the mixturefiltered, and the filtrate was extracted with CH₂Cl₂. The combinedorganic layers were washed with water, saturated NaCl solution, driedover Na₂SO₄, and concentrated to afford a residue that was purified byprecipitation from diisopropylether. The residue was transferred to anHCl salt and finally gave the product as a white solid (31 mg, 72%).

ESI-MS [M+H⁺]=375 Calculated for C₂₀H₂₆N₂O₃S=374

Example 98 1-Methyl-1H-imidazole-4-sulfonic acid[2-(7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-methyl-amidehydrochloride

1-Methyl-1H-imidazole-4-sulfonic acid[2-(7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-methyl-amidehydrochloride was prepared in analogy to example 3 and 89.

ESI-MS [M+H⁺]=455 Calculated for C₂₄H₃₀N₄O₃S=454

Example 99N-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-benzenesulfonamidehydrochloride

N-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-benzenesulfonamidehydrochloride was prepared fromN-{2-[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-benzenesulfonamidehydrochloride (example 16) in analogy to example 3 and 97.

ESI-MS [M+H⁺]=437 Calculated for C₂₅H₂₈N₂O₃S=436

Example 100 3,3,3-Trifluoro-propane-1-sulfonic acid[2-(7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-amidehydrochloride

3,3,3-Trifluoro-propane-1-sulfonic acid[2-(7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-amidehydrochloride was prepared in analogy to example 3 and 97.

ESI-MS [M+H⁺]=457 Calculated for C₂₂H₂₇F₃N₂O₃S=456

Example 101 1-Methyl-1H-imidazole-4-sulfonic acid[2-(8-benzyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-methyl-amidehydrochloride

N-(2-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-N,1-dimethyl-1H-imidazole-4-sulfonamidehydrochloride (98), 1,4-dibromobutane (49.9 mg, 0.231 mmol), andtriethylamine (31.2 mg, 0.308 mmol) were dissolved in acetonitrile (3ml) and stirred for 2 h at 130° C. in the microwave. Water and ethylacetate were added and the organic phase was separated. After extractionof the aqueous phase with ethylacetate the combined organic layers werewashed with saturated NaCl solution, dried over Na₂SO₄, and concentratedto afford a residue a residue that was purified by flash chromatography(silica gel, MeOH/CH₂Cl₂ 5:95). The residue was transferred to an HClsalt and finally gave the product as a white solid (8.5 mg, 10%) afterprecipitation from diisopropylether.

ESI-MS [M+H⁺]=509 Calculated for C₂₈H₃₆N₄O₃S=508

Example 102 Cyclopropanesulfonic acid[2-(7-amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)ethyl]-amidehydrochloride

Cyclopropanesulfonic acid[2-(7-amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)ethyl]-amidehydrochloride was prepared in analogy to example 3 and 97.

ESI-MS [M+H⁺]=401 Calculated for C₂₂H₂₈N₂O₃S=400

Example 103N-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-propionamidehydrochloride

Ethyl7-(2-aminoethoxy)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamatehydrochloride (example 2.1, 100 mg, 0.229 mmol) and N,N-dimethyl aminopyridine (30.7 mg, 0.252 mmol) were dissolved in CH₂Cl₂ (20 ml) andpropionyl chloride (30.7 mg, 0.252 mmol) was added at RT. After stirringat RT for 14 h 0.5 N HCl was added and the mixture was extracted withCH₂Cl₂. The combined organic layers were washed with saturated NaHCO₃and NaCl solution, dried over Na₂SO₄, and concentrated to afford aresidue. White solid ethyl1-(3,4-dichlorobenzyl)-7-(2-propionamidoethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(98 mg, 87%) was obtained from precipitation in ethyl acetate. Furthertransformation in analogy to example 2 and 97 finally gaveN-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-propionamidehydrochloride.

ESI-MS [M+H⁺]=353 Calculated for C₂₂H₂₈N₂O₂=352

Example 104 1-Methyl-1H-[1,2,4]triazole-3-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amide

1-Methyl-1H-[1,2,4]triazole-3-sulfonic acid{2-[7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidewas prepared in analogy to example 3.

ESI-MS [M+H⁺]=510 Calculated for C₂₂H₂₅Cl₂N₅O₃S=509

Example 105 1-Methyl-1H-imidazole-4-sulfonic acid[2-(7-azetidin-1-yl-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-methyl-amide

1-Methyl-1H-imidazole-4-sulfonic acid[2-(7-azetidin-1-yl-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-methyl-amidewas prepared in analogy to example 101.

ESI-MS [M+H⁺]=495 Calculated for C₂₇H₃₄N₄O₃S=494

Example 106N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclobutyl-methanesulfonamidehydrochloride

N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclobutyl-methanesulfonamidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=497 Calculated for C₂₄H₃₀Cl₂N₂O₃S=496

Example 107 Propane-1-sulfonic acid{2-[7-amino-8-(3-fluoro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Propane-1-sulfonic acid{2-[7-amino-8-(3-fluoro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=421 Calculated for C₂₂H₂₉FN₂O₃S=420

Example 108N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-N-methyl-methanesulfonamidehydrochloride

N-{2-[7-Amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-N-methyl-methanesulfonamidehydrochloride was prepared in analogy to example 11.

ESI-MS [M+H⁺]=497 Calculated for C₂₄H₃₀Cl₂N₂O₃S=496

Example 109 1-Methyl-1H-pyrazole-4-sulfonic acid[2-(7-amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-methyl-amide

1-Methyl-1H-pyrazole-4-sulfonic acid[2-(7-amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-methyl-amidewas prepared in analogy to example 3 and 89.

ESI-MS [M+H⁺]=455 Calculated for C₂₄H₃₀N₄O₃S=454

Example 110N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-N-ethyl-1-methyl-1H-pyrazole-4-sulfonamide

N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-N-ethyl-1-methyl-1H-pyrazole-4-sulfonamidewas prepared in analogy to example 11.

ESI-MS [M+H⁺]=537 Calculated for C₂₅H₃₀Cl₂N₄O₃S=536

Example 111 1-Methyl-1H-pyrazole-4-sulfonic acid[2-(8-benzyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-methyl-amidehydrochloride

1-Methyl-1H-pyrazole-4-sulfonic acid[2-(8-benzyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-methyl-amidehydrochloride was prepared in analogy to example 50.

ESI-MS [M+H⁺]=509 Calculated for C₂₈H₃₆N₄O₃S=508

Example 112 1-Methyl-1H-pyrazole-4-sulfonic acid[2-(7-azetidin-1-yl-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-methyl-amidehydrochloride

1-Methyl-1H-pyrazole-4-sulfonic acid[2-(7-azetidin-1-yl-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-methyl-amidehydrochloride was prepared in analogy to example 50.

ESI-MS [M+H⁺]=495 Calculated for C₂₇H₃₄N₄O₃S=494

Example 113N-(2-(7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-N-ethyl-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

N-(2-(7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-N-ethyl-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride was prepared in analogy to example 3 and 89.

ESI-MS [M+H⁺]=469 Calculated for C₂₅H₃₂N₄O₃S=468

Example 114N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)pentane-1-sulfonamidehydrochloride

N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)pentane-1-sulfonamidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=499 Calculated for C₂₄H₃₂Cl₂N₂O₃S=498

Example 115N-(2-(8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-(8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was synthesized in analogy to example 88.

ESI-MS [M+H⁺]=536 Calculated for C₂₇H₃₂Cl₂N₄O₃S=535

Example 116N-(2-(8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-(8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was prepared fromN-(2-(8-(3,4-dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(example 115) in analogy to 97.

ESI-MS [M+H⁺]=495 Calculated for C₂₇H₃₄N₄O₃S=494

Example 117, 118 (Enantiomere 1 and 2 of 116)

The racemate ofN-(2-(8-benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride (ex. 116) was separated by chiral chromatography onChiracel AD (n-heptane/ethanol 35:65, 0.1% TEA, 9 ml/min) to deliver(after transfer to the salt form)(−)-N-(2-(8-benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride ([α]=−76.0° in MeOH, c=1.040 g/100 ml [ex. 117]) and(+)-N-(2-(8-benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride ([α]=−77.7° in MeOH, c=0.382 g/100 ml ex. 118]).

ESI-MS [M+H⁺]=495 Calculated for C₂₇H₃₄N₄O₃S=494

Example 119N-(2-(8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

N-(2-(8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride was prepared fromN-(2-(8-(3,4-dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide(example 114) in analogy to 97.

ESI-MS [M+H⁺]=495 Calculated for C₂₇H₃₄N₄O₃S=494

Example 120N-(2-{[7-Amino-8-(3-chloro-4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)propane-1-sulfonamidehydrochloride

N-(2-{[7-Amino-8-(3-chloro-4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)propane-1-sulfonamidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=455 Calculated for C₂₂H₂₈ClFN₂O₃S=454

Example 121N-(2-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=415 Calculated for C₂₃H₃₀N₂O₃S=414

Example 122N-(2-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-2-cyclopropylacetamidehydrochloride

N-(2-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-2-cyclopropylacetamidehydrochloride was synthesized in analogy to example 103.

ESI-MS [M+H⁺]=447 Calculated for C₂₄H₂₈Cl₂N₂O₂=446

Example 123N-(2-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)benzamidehydrochloride

N-(2-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)benzamidehydrochloride was synthesized in analogy to example 103.

ESI-MS [M+H⁺]=469 Calculated for C₂₆H₂₆Cl₂N₂O₂=468

Example 124N-(2-{[8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-N-ethyl-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

N-(2-{[8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-N-ethyl-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride was synthesized fromN-(2-(7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-N-ethyl-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride (example 113) in analogy to example 97.

ESI-MS [M+H⁺]=523 Calculated for C₂₉H₃₈N₄O₃S=522

Example 125N-(2-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-2-cyclopropylethanesulfonamidehydrochloride

N-(2-{[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-2-cyclopropylethanesulfonamidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=497 Calculated for C₂₄H₃₀Cl₂N₂O₃S=496

Example 126C-Cyclopropyl-N-{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-N-methyl-methanesulfonamidehydrochloride

C-Cyclopropyl-N-{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-N-methyl-methanesulfonamidehydrochloride was synthesized in analogy to examples 89, 97, 101.

ESI-MS [M+H⁺]=551 Calculated for C₂₈H₃₆Cl₂N₂O₃S=550

Example 127N-(2-{[8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropyl-N-methylmethanesulfonamidehydrochloride

N-(2-{[8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropyl-N-methylmethanesulfonamidehydrochloride was synthesized from1-cyclopropyl-N-(2-{[8-(3,4-dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-N-methylmethanesulfonamidehydrochloride in analogy to example 97.

ESI-MS [M+H⁺]=483 Calculated for C₂₈H₃₈N₂O₃S=482

Example 128N-(2-{[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-{[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=449 Calculated for C₂₃H₂₉ClN₂O₃S=448

Example 129N-(2-{[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropyl-N-methylmethanesulfonamidehydrochloride

N-(2-{[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropyl-N-methylmethanesulfonamidehydrochloride was prepared in analogy to example 3, N-methylation wasperformed according to 89.

ESI-MS [M+H⁺]=463 Calculated for C₂₄H₃₁ClN₂O₃S=462

Example 130N-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-C-cyclopropyl-N-methyl-methanesulfonamidehydrochloride

N-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-C-cyclopropyl-N-methyl-methanesulfonamidehydrochloride was prepared fromN-(2-{[7-amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropyl-N-methylmethanesulfonamidehydrochloride (example 108) in analogy to example 97.

ESI-MS [M+H⁺]=429 Calculated for C₂₄H₃₂N₂O₃S=428

Example 131N-(2-{[7-Amino-8-(3,4-difluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-{[7-Amino-8-(3,4-difluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was prepared in analogy to example 3.

ESI-MS [M+H⁺]=451 Calculated for C₂₃H₂₈F₂N₂O₃S=450

Example 132C-Cyclopropyl-N-{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-methanesulfonamidehydrochloride

C-Cyclopropyl-N-{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-methanesulfonamidehydrochloride was prepared in analogy to example 88.

ESI-MS [M+H⁺]=537 Calculated for C₂₇H₃₄Cl₂N₂O₃S=536

Example 133N-(2-{[8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-{[8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was prepared fromC-cyclopropyl-N-{2-[8-(3,4-dichloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-methanesulfonamidehydrochloride (example 132) in analogy to example 97.

ESI-MS [M+H⁺]=469 Calculated for C₂₇H₃₆N₂O₃S=468

Example 1341-Cyclopropyl-N-[2-({8-(3,4-dichlorobenzyl)-7-[3-fluoropyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)ethyl]methanesulfonamide

7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-ol (691mg, 2.146 mmol, example 34), 2 eq of 1,4-dibromo-2-fluorobutane, and 3eq of triethylamine were dissolved in acetonitrile (10 ml) and heated inthe microwave for 2 h. Addition of water with ethylacetate, washing ofthe organic phase with saturated NaHCO₃, NaCl, drying over Na₂SO₄ andflash chromatography (silica gel, CH₂Cl₂/MeOH 95:5) gave8-(3,4-dichlorobenzyl)-7-(3-fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol(330 mg, 39%). The ethylene sulfonamide side chain was added in analogyto examples 1, 7, 8 to give1-cyclopropyl-N-[2-({8-(3,4-dichlorobenzyl)-7-[3-fluoropyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)ethyl]methanesulfonamide.

ESI-MS [M+H⁺]=555 Calculated for C₂₇H₃₃Cl₂FN₂O₃S=554

Example 135N-(2-{[7-(Azetidin-1-yl)-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamide

N-(2-{[7-(Azetidin-1-yl)-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidewas prepared in analogy to example 320.

ESI-MS [M+H⁺]=523 Calculated for C₂₆H₃₂Cl₂N₂O₃S=522

Example 136N-[2-({8-Benzyl-7-[3-fluoropyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)ethyl]-1-cyclopropylmethanesulfonamidehydrochloride

N-[2-({8-Benzyl-7-[3-fluoropyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)ethyl]-1-cyclopropylmethanesulfonamidehydrochloride was synthesized from1-cyclopropyl-N-[2-({8-(3,4-dichlorobenzyl)-7-[3-fluoropyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)ethyl]methanesulfonamide(example 134) in analogy to 97.

ESI-MS [M+H⁺]=487 Calculated for C₂₇H₃₆FN₂O₃S=486

Example 137N-(2-{[8-Benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

The synthesis was performed starting from ethyl1-benzyl-7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(synthesized in analogy to example 3), which was dissolved in THF (50ml), after which LiAlH₄ was added at room temperature and the mixturewas stirred for 8 h under reflux. Addition of 2N aqueous NaOH,extraction with CH₂Cl₂, washing of the organic layers with saturatedNaHCO₃ solution and saturated NaCl solution and evaporation of thesolvent gave a residue that was treated with iPrOH/HCl after which theproduct precipitated. After filtration a white salt (287 mg, 58%) wereobtained.

ESI-MS [M+H⁺]=429 Calculated for C₂₄H₃₂N₂O₃S=428

Example 1381-Cyclopropyl-N-(2-{[8-(3-fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)methanesulfonamidehydrochloride

1-Cyclopropyl-N-(2-{[8-(3-fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)methanesulfonamidehydrochloride was synthesized in analogy to examples 264/88.

ESI-MS [M+H⁺]=487 C₂₇H₃₅FN₂O₃S=486

Example 139N-(2-{[7-(Azetidin-1-yl)-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-{[7-(Azetidin-1-yl)-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was synthesized in analogy to example 320.

ESI-MS [M+H⁺]=473 C₂₆H₃₃FN₂O₃S=472

Example 140N-(2-{[8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-{[8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was synthesized in analogy to examples 264/88

ESI-MS [M+H⁺]=513 C₂₇H₃₃FN₄O₃S=512

Example 141N-(2-{[7-(Azetidin-1-yl)-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-{[7-(Azetidin-1-yl)-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was synthesized in analogy to example 320.

ESI-MS [M+H⁺]=499 C₂₆H₃₁FN₄O₃S=498

Example 142N-(2-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was synthesized in analogy to example 320.

ESI-MS [M+H⁺]=455 C₂₆H₃₄N₂O₃S=454

Examples 143, 144 (Enantiomeres 1 and 2 of example 142)

The racemate ofN-(2-{[7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride (example 142) was separated by chiral chromatography onChiracel AD (n-heptane/ethanol 35:65, 0.1% TEA, 9 ml/min) to deliver(after transfer to salt form)(−)-N-(2-(7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-cyclopropylmethanesulfonamide([α]=−103.0° in MeOH, c=0.461 g/100 ml [example 143]) and(+)-N-(2-(7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-cyclopropylmethanesulfonamidesuccinate ([α]=+57.0° in MeOH, c=0.508 g/100 ml [example 144])

ESI-MS [M+H⁺]=455 C₂₆H₃₄N₂O₃S=454

Example 145N-(2-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide

N-(2-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidewas synthesized in analogy to example 320.

ESI-MS [M+H⁺]=481 C₂₆H₃₂N₄O₃S=480

Example 146

The racemate ofN-(2-{[7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide(145) can be separated by chiral chromatography to deliver (aftertransfer to the salt form)(−)-N-(2-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidefumarate ([α]=−81.4° in MeOH, c=0.409 g/100 ml).

ESI-MS [M+H⁺]=481 Calculated for C₂₇H₃₄N₄O₃S=480

Example 147N-(2-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)cyclobutanesulfonamide

N-(2-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)cyclobutanesulfonamidewas synthesized in analogy to example 320.

ESI-MS [M+H⁺]=455 C₂₆H₃₄N₂O₃S=454

Example 148 Propane-1-sulfonic acid[2-(7-azetidin-1-yl-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-amide

Propane-1-sulfonic acid[2-(7-azetidin-1-yl-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-amidewas synthesized in analogy to example 320.

ESI-MS [M+H⁺]=443 C₂₅H₃₄N₂O₃S=442

Example 149N-(2-{[8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamidehydrochloride

N-(2-{[8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamidehydrochloride was synthesized in analogy to examples 264/88.

ESI-MS [M+H⁺]=512 C₂₈H₃₄FN₃O₃S=511

Example 150N-(2-{[7-Amino-8-(3-chloro-5-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-{[7-Amino-8-(3-chloro-5-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was synthesized in analogy to example 3.

ESI-MS [M+H⁺]=467 C₂₃H₂₈ClFN₂O₃S=466

Example 151N-(2-{[7-Amino-8-(3-chloro-5-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-{[7-Amino-8-(3-chloro-5-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was synthesized in analogy to example 3.

ESI-MS [M+H⁺]=493 C₂₃H₂₆ClFN₄O₃S=492

Example 152N-[2-({8-Benzyl-7-[3-fluoropyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)ethyl]-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-[2-({8-Benzyl-7-[3-fluoropyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)ethyl]-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was synthesized in analogy to 264/88.

ESI-MS [M+H⁺]=513 C₂₇H₃₃FN₄O₃S=512

Example 153N-(2-{[8-(3-Cyanobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide

N-(2-{[8-(3-Cyanobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidewas synthesized in analogy to 264/88.

ESI-MS [M+H⁺]=520 C₂₈H₃₃N₅O₃S=519

Example 154N-(2-{[8-(3-Cyanobenzyl)-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-{[8-(3-Cyanobenzyl)-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was synthesized in analogy to example 88.

ESI-MS [M+H⁺]=508 C₂₇H₃₃N₅O₃S=507

Example 155N-(2-{[8-(3-Cyanobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-{[8-(3-Cyanobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was synthesized in analogy to examples 264/88.

ESI-MS [M+H⁺]=494 C₂₈H₃₅N₃O₃S=493

Example 156N-(2-{[8-(3-Cyanobenzyl)-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

N-(2-{[8-(3-Cyanobenzyl)-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride was synthesized in analogy to example 88.

ESI-MS [M+H⁺]=482 C₂₇H₃₅N₃O₃S=481

Example 157N-(2-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)propane-1-sulfonamidehydrochloride

N-(2-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)propane-1-sulfonamidehydrochloride was synthesized from Propane-1-sulfonic acid{2-(7-amino-8-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride (example 8) in analogy to example 97.

ESI-MS [M+H⁺]=403 C₂₂H₃₀N₂O₃S=402

Example 158N-(2-{[8-(3-Chloro-5-fluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

The synthesis was performed starting from ethyl1-(3-chloro-5-fluorobenzyl)-7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(synthesized in analogy to example 3), which was dissolved in THF (50ml), after which LiAlH₄ was added at room temperature and the mixturewas stirred for 8 h under reflux. Addition of 2N aqueous NaOH,extraction with CH₂Cl₂, washing of the organic layers with saturatedNaHCO₃ solution and saturated NaCl solution and evaporation of thesolvent gave a residue that was treated with iPrOH/HCl after which theproduct precipitated. After filtration a white salt (134 mg, 39%) wasobtained.

ESI-MS [M+H⁺]=481 Calculated for C₂₄H₃₀ClFN₂O₃S=480

Example 159N-(2-{[7-(Azetidin-1-yl)-8-(3-chloro-5-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamide(2E)-but-2-enedioate

N-(2-{[7-(Azetidin-1-yl)-8-(3-chloro-5-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamide(2E)-but-2-enedioate was synthesized in analogy to example 320.

ESI-MS [M+H⁺]=507 C₂₆H₃₂ClFN₂O₃S=506

Example 160N-(2-{[7-(Azetidin-1-yl)-8-(3-chloro-5-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide(2E)-but-2-enedioate

N-(2-{[7-(Azetidin-1-yl)-8-(3-chloro-5-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide(2E)-but-2-enedioate was synthesized in analogy to example 320.

ESI-MS [M+H⁺]=533 C₂₆H₃₀ClFN₄O₃S=532

Example 1611-Cyclopropyl-N-(2-{[8-(4-fluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)methanesulfonamide

The synthesis was performed starting from ethyl7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1-(4-fluorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(synthesized in analogy to example 3), which was dissolved in THF (50ml), after which LiAlH₄ was added at room temperature and the mixturewas stirred for 8 h under reflux. Addition of 2N aqueous NaOH,extraction with CH₂Cl₂, washing of the organic layers with saturatedNaHCO₃ solution and saturated NaCl solution and evaporation of thesolvent gave a residue that was treated with iPrOH/HCl after which theproduct precipitated. After filtration a white salt (89 mg, 76%) wasobtained.

ESI-MS [M+H⁺]=447 C₂₄H₃₁FN₂O₃S=446

Example 162(−)-N-(2-(8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

The synthesis was performed starting from (−)-ethyl1-benzyl-7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(137), which was dissolved in THF (50 ml), after which LiAlH₄ was addedat room temperature and the mixture was stirred for 8 h under reflux.Addition of 2N aqueous NaOH, extraction with CH₂Cl₂, washing of theorganic layers with saturated NaHCO₃ solution and saturated NaClsolution and evaporation of the solvent gave a residue that was treatedwith iPrOH/HCl after which the product precipitated. After filtration awhite salt (102 mg, 79%) was obtained. The racemate was separated bychiral chromatography on Chiracel AD (n-heptane/ethanol/tert-butanol800:150:50) to deliver (after transfer to the salt form)(−)-N-(2-(8-benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride ([α]=−80.5° in MeOH, c=0.191 g/100 ml)

ESI-MS [M+H⁺]=429 C₂₄H₃₂N₂O₃S=428

Example 1631-Methyl-N-(2-{[8-(3-methylbenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1H-imidazole-4-sulfonamide

1-Methyl-N-(2-{[8-(3-methylbenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1H-imidazole-4-sulfonamidewas synthesized in analogy to 264/88.

ESI-MS [M+H⁺]=509 C₂₈H₃₆N₄O₃S=508

Example 164N-(2-{[8-(3-Methoxybenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

N-(2-{[8-(3-Methoxybenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride was synthesized in analogy to examples 264/88.

ESI-MS [M+H⁺]=525 C₂₈H₃₆N₄O₄S=524

Example 165 1-Methyl-1H-imidazole-4-sulfonic acid{2-[7-amino-8-(3-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

1-Methyl-1H-imidazole-4-sulfonic acid{2-[7-amino-8-(3-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride was synthesized in analogy to example 3.

ESI-MS [M+H⁺]=509 C₂₄H₂₇F₃N₄O₃S=508

The following examples were prepared in analogy to example 40:

Example 166N-{[7-Amino-8-(3-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=407 Calculated for C₂₁H₂₇ClN₂O₂S=406

Example 167N-[(7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]methanesulfonamidehydrochloride

ESI-MS [M+H⁺]=345 Calculated for C₁₉H₂₄N₂O₂S=344

Example 168N-[(7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]benzenesulfonamidehydrochloride

ESI-MS [M+H⁺]=407 Calculated for C₂₄H₂₆N₂O₂S=406

Example 169 Enantiomer 2 ofN-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

The compound was obtained by chiral chromatography (Chiralpak AD-H 30 mmID×250 mm, n-hexane/EtOH/MeOH/diethylamine=20/40/40/0.1) from theracemic compound (example 42) as the first eluting peak. Opticalrotation=−50° (589 nm, 25° C., c=0.1 in methanol).

ESI-MS [M+H⁺]=373 Calculated for C₂₁H₂₈N₂O₂S=372

Example 170 Enantiomer 1 ofN-{[7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

The compound was obtained by chiral chromatography (Chiralpak AD-H 30 mmID×250 mm, n-hexane/EtOH/MeOH/diethylamine=20/40/40/0.1) from theracemic compound (example 42) as the second eluting peak. Opticalrotation=+49° (589 nm, 25° C., c=0.1 in methanol).

ESI-MS [M+H⁺]=373 Calculated for C₂₁H₂₈N₂O₂S=372

Example 171N-{[7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=391 Calculated for C₂₁H₂₇FN₂O₂S=390

Example 172N-[(7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

ESI-MS [M+H⁺]=411 Calculated for C₂₂H₂₆N₄O₂S=410

Example 173N-[(7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

ESI-MS [M+H⁺]=411 Calculated for C₂₂H₂₆N₄O₂S=410

Example 174N-{[7-Amino-8-(4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}cyclobutanesulfonamidehydrochloride

ESI-MS [M+H⁺]=403 Calculated for C₂₂H₂₇FN₂O₂S=402

Example 175N-{[7-Amino-8-(4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=391 Calculated for C₂₁H₂₇FN₂O₂S=390

Example 176N-{[7-Amino-8-(4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

ESI-MS [M+H⁺]=429 Calculated for C₂₂H₂₅FN₄O₂S=428

Example 177N-{[7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

ESI-MS [M+H⁺]=429 Calculated for C₂₂H₂₅FN₄O₂S=428

Example 178N-{[7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

ESI-MS [M+H⁺]=429 Calculated for C₂₂H₂₅FN₄O₂S=428

Example 179N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-3-methylbenzenesulfonamidehydrochloride

ESI-MS [M+H⁺]=421 Calculated for C₂₅H₂₈N₂O₂S=420

Example 180N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-pyrrole-3-sulfonamidehydrochloride

ESI-MS [M+H⁺]=410 Calculated for C₂₃H₂₇N₃O₂S=409

Example 181N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}pyridine-3-sulfonamidedihydrochloride

ESI-MS [M+H⁺]=408 Calculated for C₂₃H₂₅N₃O₂S=407

Example 182N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamidehydrochloride

ESI-MS [M+H⁺]=479 Calculated for C₂₃H₂₅F₃N₄O₂S=478

Example 183N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-pyrazole-3-sulfonamidehydrochloride

ESI-MS [M+H⁺]=411 Calculated for C₂₂H₂₆N₄O₂S=410

Example 184N-{[7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}cyclobutanesulfonamidehydrochloride

ESI-MS [M+H⁺]=403 Calculated for C₂₂H₂₇FN₂O₂S=402

Example 185N-{[7-Amino-8-(3,4-difluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-cyclopropylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=421 Calculated for C₂₂H₂₆F₂N₂O₂S=420

Example 186N-{[7-Amino-8-(3,4-difluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}cyclobutanesulfonamidehydrochloride

ESI-MS [M+H⁺]=421 Calculated for C₂₂H₂₆F₂N₂O₂S=420

Example 187N-{[8-Benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

tert-Butyl[1-benzyl-7-{[(propylsulfonyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl]carbamateprepared in analogy to example 39 (1240 mg, 2.62 mmol) was dissolved intetrahydrofuran (50 mL). A solution of lithium aluminium hydride (1 M intetrahydrofuran, 7.87 mL, 7.87 mmol) was added dropwise at roomtemperature. The reaction mixture was then heated to 60° C. for 1 h.Aqueous work-up, purification of the extracted product by flashchromatography (silica gel, dichloromethane, methanol) and treatmentwith 1.25 M hydrochloric acid in ethanol followed by concentration invacuo gave the desired product.

Yield: 590 mg (1.4 mmol, 53%).

ESI-MS [M+H⁺]=425 Calculated for C₂₂H₃₀N₂O₂S=424

In analogy to example 187 the following examples were prepared:

Example 188N-{[8-Benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}cyclobutanesulfonamidehydrochloride

ESI-MS [M+H⁺]=400 Calculated for C₂₃H₃₀N₂O₂S=399

Example 189N-{[8-Benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-3-methylbenzenesulfonamidehydrochloride

ESI-MS [M+H⁺]=435 Calculated for C₂₆H₃₀N₂O₂S=434

Example 190N-{[8-Benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-pyrrole-3-sulfonamidehydrochloride

ESI-MS [M+H⁺]=424 Calculated for C₂₄H₂₉N₃O₂S=423

Example 191N-{[8-Benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-pyrazole-3-sulfonamidehydrochloride

ESI-MS [M+H⁺]=425 Calculated for C₂₃H₂₈N₄O₂S=424

Example 192 Enantiomer 1 ofN-{[8-benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

A chiral building block, i.e. an enantiomer of tert-butyl(1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate

was used for the synthesis.

tert-Butyl (1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamatecan be prepared in analogy to the dichloroderivative described inexample 34. The cis-isomer can be separated into the enantiomers bychiral chromatography (Daicel, Chiralpak IC, 250×4, 6 mm ID, 5μ,n-heptane/ethanol=1/9 with 0.1% triethylamine). The enantiomer elutingsecond was used in the syntheses described above.

ESI-MS [M+H⁺]=387 Calculated for C₂₂H₃₀N₂O₂S=386

Example 193 Enantiomer 1 ofN-{[8-benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}cyclobutanesulfonamidehydrochloride

The enantiomer of tert-butyl(1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate describedin example 192 was as chiral building block for the synthesis.

ESI-MS [M+H⁺]=399 Calculated for C₂₃H₃₀N₂O₂S=398

Example 194N-{[trans-8-Benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

Prepared from the trans derivative obtained as a by-product in therecrystallization of

(cf. example 1).

ESI-MS [M+H⁺]=387 Calculated for C₂₂H₃₀N₂O₂S=386

Example 195N-{[8-Benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

ESI-MS [M+H⁺]=425 Calculated for C₂₃H₂₈N₄O₂S=424

Example 196N-(1-Benzyl-7-{[(propylsulfonyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide

N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamide(cf. example 42) was acetylated in dichloromethane with acetyl chloridein the presence of ethyldiisopropylamine at room temperature.

ESI-MS [M+H⁺]=415 Calculated for C₂₃H₃₀N₂O₃S=414

Example 197N-[(1-(4-Fluorobenzyl)-7-({[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}methyl)-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide

This compound was prepared in analogy to example 196.

ESI-MS [M+H⁺]=471 Calculated for C₂₄H₂₇FN₄O₃S=470

Example 198N-{[8-Benzyl-7-(ethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamidehydrochloride

N-(1-Benzyl-7-{[(propylsulfonyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide(example 196, 153 mg, 0.37 mmol) was dissolved in tetrahydrofuran (5mL). 1 M Boran dimethylsulfide complex solution in tetrahydrofuran (852μL, 8.52 mmol) was added and the reaction mixture stirred at roomtemperature over night. Water was added and the mixture extracted withdichloromethane (three times). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo. The crude product was purified byflash chromatography (silica gel, dichloromethane, methanol). Excess 6 Mhydrochloric acid in isopropanol was added. The solvent was evaporatedand the product dried in vacuo. Yield: 70 mg (0.16 mmol, 36%).

ESI-MS [M+H⁺]=401 Calculated for C₂₃H₃₂N₂O₂S=400

The following examples were prepared in analogy to example 198:

Example 199 1-Methyl-1H-imidazole-4-sulfonic acid[7-ethylamino-8-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl]-amidehydrochloride

ESI-MS [M+H⁺]=457 Calculated for C₂₄H₂₉FN₄O₂S=456

Example 200 1-Methyl-1H-pyrazole-4-sulfonic acid[7-ethylamino-8-(3-fluoro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-amidehydrochloride

ESI-MS [M+H⁺]=457 Calculated for C₂₄H₂₉FN₄O₂S=456

Example 201N-{3-[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride 201.1 tert-Butyl[1-(4-chlorobenzyl)-7-{3-[(propylsulfonyl)amino]propyl}-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

To a solution of 9-BBN (0.5 M in tetrahydrofuran, 8.85 mL, 4.42 mmol)was added dropwise a solution N-allylpropane-1-sulfonamide (1152 mg,7.06 mmol) in tetrahydrofuran (1 mL) a 0° C. After stirring at 0° C. to5° C. for 3.5 hours dioxane (25 mL) was added followed by7-(tert-butoxycarbonylamino)-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (1000 mg, 1.923 mmol, prepared analogously toexample 34.3), palladium acetate (43.2 mg, 0.192 mmol),triphenylphosphine (101 mg, 0.385 mmol) and cesium carbonate (1253 mg,3.85 mmol). The yellow reaction mixture was heated under reflux for 3hours. The reaction mixture was diluted with ethyl acetate (60 mL) andwashed with water (2×40 mL). The organic layer was dried andconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, dichloro methane, methanol).

Yield: 854 mg (1.596 mmol, 83%).

201.2N-{3-[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

tert-Butyl[1-(4-chlorobenzyl)-7-{3-[(propylsulfonyl)amino]propyl}-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(150 mg, 0.281 mmol) was dissolved in dichloromethane (3 mL) and asolution of hydrochloric acid (0.5 mL, 5 M in isopropanol) was added.After stirring at room temperature for 2 hours the solvent was removedin vacuo. Water was added (15 mL) and the pH was adjusted to 9 withaqueous saturated sodium bicarbonate and the mixture was extracted withdichloromethane (3×15 mL). The combined organic extracts were dried andconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, dichloromethane, methanol). The product wasdissolved in dichloromethane (2 mL) and a solution of hydrochloric acidin ethanol (1.25 M) was added. The solvent was removed in vacuo. Yield:31.4 mg (0.187 mmol, 36%).

ESI-MS [M+H⁺]=435 Calculated for C₂₃H₃₁ClN₂O₂S=434

The following examples were prepared in analogy to example 201:

Example 202N-{3-[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=447 Calculated for C₂₄H₃₁ClN₂O₂S=446

Example 203N-{3-[7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=469 Calculated for C₂₃H₃₀Cl₂N₂O₂S=468

Example 204N-{3-[7-Amino-8-(3,4-difluoro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-propyl}-C-cyclopropyl-methanesulfonamidehydrochloride

ESI-MS [M+H⁺]=449 Calculated for C₂₄H₃₀F₂N₂O₂S=448

Example 205N-{3-[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=401 Calculated for C₂₃H₃₂N₂O₂S=400

Example 206N-{3-[7-Amino-8-(3,4-difluoro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=437 Calculated for C₂₃H₃₀F₂N₂O₂S=436

Example 207N-{3-[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamidetrifluoroacetate

ESI-MS [M+H⁺]=413 Calculated for C₂₄H₃₂N₂O₂S=412

Example 208N-{3-[7-Amino-8-(4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=431 Calculated for C₂₄H₃₁FN₂O₂S=430

Example 209N-{3-[7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=419 Calculated for C₂₃H₃₁FN₂O₂S=418

Example 210N-{3-[7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=431 Calculated for C₂₄H₃₁FN₂O₂S=430

Example 211 N-{3-[7-Amino-8-(2-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamide hydrochloride

ESI-MS [M+H⁺]=435 Calculated for C₂₃H₃₁ClN₂O₂S=434

Example 212N-{3-[7-Amino-8-(2-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-propyl}-C-cyclopropyl-methanesulfonamidehydrochloride

ESI-MS [M+H⁺]=447 Calculated for C₂₄H₃₁ClN₂O₂S=446

Example 213N-{3-[7-Amino-8-(4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=419 Calculated for C₂₃H₃₁FN₂O₂S=418

Example 214N-[1-(3-Fluorobenzyl)-7-{3-[(propylsulfonyl)amino]propyl}-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide

N-(3-(7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl)propyl)propane-1-sulfonamide(cf. example 209: 45 mg, 0.108 mmol) and triethylamine (15 μL, 0.108mmol) were dissolved in dichloromethane (2 mL). Acetylchloride (7.64 μL,0.108 mmol) were added. The reaction mixture was stirred for 12 hours atroom temperature. The reaction mixture was diluted with dichloromethaneand successively washed with hydrochloric acid, water and saturatedsodium chloride solution. The organic layer was dried and concentratedin vacuo. The crude product was purified by flash-chromatography (silicagel, dichloromethane, methanol). Yield: 37 mg (0.08 mmol, 75%).

ESI-MS [M+H⁺]=461 Calculated for C₂₅H₃₃FN₂O₃S=460

In analogy to example 214 the following examples were prepared:

Example 215N-[1-(4-Fluorobenzyl)-7-{3-[(propylsulfonyl)amino]propyl}-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide

ESI-MS [M+H⁺]=461 Calculated for C₂₅H₃₃FN₂O₃S=460

Example 216N-[1-Benzyl-7-(3-{[(cyclopropylmethyl)sulfonyl]amino}propyl)-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide

ESI-MS [M+H⁺]=455 Calculated for C₂₆H₃₄N₂O₃S=454

Example 217N-[1-Benzyl-7-{3-[(propylsulfonyl)amino]propyl}-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide

ESI-MS [M+H⁺]=443 Calculated for C₂₆H₃₄N₂O₃S=442

Example 218N-[7-(3-{[(Cyclopropylmethyl)sulfonyl]amino}propyl)-1-(3-fluorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide

ESI-MS [M+H⁺]=473 Calculated for C₂₆H₃₃FN₂O₃S=472

Example 219 Propane-1-sulfonic acid{3-[7-ethylamino-8-(3-fluoro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-propyl}-amidehydrochloride

N-(1-(3-Fluorobenzyl)-7-(3-(propylsulfonamido)propyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide(cf. example 214, 19.5 mg, 0.042 mmol) was dissolved in tetrahydrofuran(1 mL) and borane dimethylsulfide (106 μL, 0.212 mmol) was added. Thereaction mixture was stirred for 5 hours at 50° C. After cooling to roomtemperature aqueous hydrochloric acid was added. The mixture was madealkaline by the addition of sodium bicarbonate and extracted severaltimes with dichloromethane. The combined organic extracts were dried(MgSO₄), concentrated in vacuo and the crude product purified byflash-chromatography (silica gel, dichloromethane, methanol). An excessof 1 M hydrochloric acid in ether was added to the purified product andthe ether distilled off. Yield: 7 mg (0.016 mmol, 37%).

ESI-MS [M+H⁺]=447 Calculated for C₂₅H₃₅FN₂O₂S=446

The following examples were prepared in analogy to example 219:

Example 220N-{3-[7-(Ethylamino)-8-(4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=447 Calculated for C₂₅H₃₅FN₂O₂S=446

Example 221C-Cyclopropyl-N-{3-[7-ethylamino-8-(3-fluoro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-propyl}-methanesulfonamidehydrochloride

ESI-MS [M+H⁺]=459 Calculated for C₂₆H₃₅FN₂O₂S=458

Example 222 Propane-1-sulfonic acid{3-[8-(2-chloro-benzyl)-7-ethylamino-5,6,7,8-tetrahydronaphthalen-2-yl]-propyl}-amidehydrochloride

ESI-MS [M+H⁺]=463 Calculated for C₂₅H₃₅ClN₂O₂S=462

Example 223N-{3-[8-Benzyl-7-(ethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=429 Calculated for C₂₅H₃₆N₂O₂S=428

Example 224N-{3-[8-Benzyl-7-(ethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=441 Calculated for C₂₆H₃₆N₂O₂S=440

Example 225N-{3-[8-(3,4-Difluorobenzyl)-7-(ethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidetrifluoroacetate

ESI-MS [M+H⁺]=465 Calculated for C₂₆H₃₄F₂N₂O₂S=464

Example 2261-Cyclopropyl-N-{3-[8-(3,4-difluorobenzyl)-7-(ethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}methanesulfonamidetrifluoroacetate

ESI-MS [M+H⁺]=477 Calculated for C₂₆H₃₄F₂N₂O₂S=476

Example 227N-{3-[7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-N-methylpropane-1-sulfonamidehydrochloride

tert-Butyl(1-(3-fluorobenzyl)-7-(3-(propylsulfonamido)propyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(cf. 209 and 201a, 65 mg, 0.125 mmol) was dissolved in acetonitrile (800μL) and methyl iodide (24 μL, 0.376 mmol) and cesium carbonate (0.102 g,0.313 mmol) was added. The reaction mixture was heated for 24 hours in asealed vessel to 80° C. The reaction mixture was diluted with ethylacetate. The ethyl acetate solution was successively washed with waterand saturated sodium chloride solution. The organic phase was dried(MgSO4) and concentrated in vacuo. The crude product was purified bypreparative thin-layer chromatography (silica gel, dichloromethane,methanol). The obtained tert-butyl1-(3-fluorobenzyl)-7-(3-(N-methylpropylsulfonamido)propyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(65 mg, 0.122 mmol) was dissolved in 4 M hydrochloric acid inisopropanol and stirred at room temperature for 4 hours. The solvent wasremoved in vacuo. Diethyl ether was added and the precipitate removed byfiltration and dried. Yield: 22 mg (0.047 mmol, 38%).

ESI-MS [M+H⁺]=433 Calculated for C₂₄H₃₃FN₂O₂S=432

The following examples were prepared in analogy to example 227:

Example 228N-{3-[7-Amino-8-(2-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-propyl}-C-cyclopropyl-N-methyl-methanesulfonamidehydrochloride

ESI-MS [M+H⁺]=461 Calculated for C₂₅H₃₃ClN₂O₂S=460

Example 229 Propane-1-sulfonic acid{3-[7-amino-8-(2-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-propyl}-methyl-amidehydrochloride

ESI-MS [M+H⁺]=449 Calculated for C₂₄H₃₃ClN₂O₂S=448

Example 230N-{3-[7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropyl-N-methylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=445 Calculated for C₂₅H₃₃FN₂O₂S=444

Example 231N-{3-[7-Amino-8-(4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropyl-N-methylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=445 Calculated for C₂₅H₃₃FN₂O₂S=444

Example 232N-{3-[7-Amino-8-(4-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-N-methylpropane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=433 Calculated for C₂₄H₃₃FN₂O₂S=432

Example 233N-{3-[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropyl-N-methylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=461 Calculated for C₂₅H₃₃ClN₂O₂S=460

Example 234N-{3-[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-N-methylpropane-1-sulfonamidehydrochloride

ESI-MS [M+H⁺]=449 Calculated for C₂₄H₃₃ClN₂O₂S=448

Example 235 was prepared in analogy to example 47:

N-(2-{[7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-cyclopropylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=433 Calculated for C₂₃H₂₉FN₂O₃S=432

The following examples were prepared in analogy to example 46:

Example 236 Ethyl[1-(3,5-difluorobenzyl)-7-(2-{[(1-methyl-1H-pyrrol-3-yl)sulfonyl]amino}ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

ESI-MS [M+H⁺]=548 Calculated for C₂₇H₃₁F₂N₃O₅S=547

Example 237 Ethyl[7-(2-{[(cyclopropylmethyl)sulfonyl]amino}ethoxy)-1-(3,5-difluorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

ESI-MS [M+H⁺]=523 Calculated for C₂₆H₃₂F₂N₂O₅S=522

Example 238 was prepared in analogy to example 47:

Enantiomer 1 ofN-(2-{[7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

Could be separated by chiral chromatography of the final compound or anintermediate.

ESI-MS [M+H⁺]=441 Calculated for C₂₃H₂₈N₄O₃S=440

The following examples were prepared in analogy to example 137:

Example 239 Enantiomer 2 ofC-cyclopropyl-N-{2-[8-(3-fluoro-benzyl)-7-methylamino-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-methanesulfonamidehydrochloride

C-Cyclopropyl-N-{2-[8-(3-fluoro-benzyl)-7-methylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-methanesulfonamide(Daicel, Chiralpak IC, 250×4, 6 mm ID, 5μ, methyl t-butylether/dichloromethane/methanol/triethylamine=900/50/50/1). The secondeluting enantiomer was used for synthesis of the final compound.

ESI-MS [M+H⁺]=447 Calculated for C₂₄H₃₁FN₂O₃S=446

Example 240 Enantiomer 1 of1-cyclopropyl-N-(2-{[8-(3-fluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)methanesulfonamidehydrochloride

Ethyl7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1-(3-fluorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamatewas separated by chiral chromatography (Daicel, Chiralpak IC, 250×4,6 mmID, methyl t-butylether/dichloromethane/methanol/triethylamine=900/50/50/1). The firsteluting enantiomer was used for synthesis of the final compound.

ESI-MS [M+H⁺]=447 Calculated for C₂₄H₃₁FN₂O₃S=446

Example 241 Enantiomer 1 ofN-(2-{[8-(3,5-difluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamidehydrochloride

Ethyl1-(3,5-difluorobenzyl)-7-(2-(1-methyl-1H-pyrrole-3-sulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamatewas separated by chiral chromatography (Daicel, Chiralpak AD, 250×20 mmID, 10μ, n-heptane/ethanol/triethylamine=35/65/1). The second elutingenantiomer was used for synthesis of the final compound.

Can be separated by chiral chromatography of the final compound or anintermediate.

ESI-MS [M+H⁺]=490 Calculated for C₂₅H₂₉F₂N₃O₃S=489

Example 242 Enantiomer 2 ofN-(2-{[8-(3,5-difluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamidehydrochloride

Ethyl1-(3,5-difluorobenzyl)-7-(2-(1-methyl-1H-pyrrole-3-sulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamatewas separated by chiral chromatography (Daicel, Chiralpak AD, 250×20 mmID, 10μ, n-heptane/ethanol/triethylamine=35/65/1). The first elutingenantiomer was used for synthesis of the final compound.

ESI-MS [M+H⁺]=490 Calculated for C₂₅H₂₉F₂N₃O₃S=489

Example 2431-Cyclopropyl-N-(2-{[8-(3,5-difluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)methanesulfonamidehydrochloride

ESI-MS [M+H⁺]=465 Calculated for C₂₄H₃₀F₂N₂O₃S=464

Example 244 Enantiomer 2 of1-cyclopropyl-N-(2-{[8-(3,5-difluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)methanesulfonamidehydrochloride

Ethyl7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1-(3,5-difluorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamatewas separated by chiral chromatography (Daicel, Chiralpak AD, 250×20 mmID, 10μ, n-heptane/ethanol/t-butanol=800/150/50). The first elutingenantiomer was used for synthesis of the final compound.

ESI-MS [M+H⁺]=465 Calculated for C₂₄H₃₀F₂N₂O₃S=464

Example 245 Enantiomer 1 of1-cyclopropyl-N-(2-{[8-(3,5-difluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)methanesulfonamidehydrochloride

Ethyl7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1-(3,5-difluorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamatewas separated by chiral chromatography (Daicel, Chiralpak AD, 250×20 mmID, 10μ, n-heptane/ethanol/t-butanol=800/150/50). The second elutingenantiomer was used for synthesis of the final compound.

ESI-MS [M+H⁺]=465 Calculated for C₂₄H₃₀F₂N₂O₃S=464

Example 246N-(2-{[8-(3,5-Difluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamidehydrochloride

ESI-MS [M+H⁺]=490 Calculated for C₂₅H₂₉F₂N₃O₃S=489

Example 2471-Cyclopropyl-N-(2-{[8-(3-fluorobenzyl)-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)methanesulfonamidehydrochloride

ESI-MS [M+H⁺]=447 Calculated for C₂₄H₃₁FN₂O₃S=446

Example 248N-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide248.1 7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

Tert-butyl 1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(1.1 g, 3.03 mmol) was dissolved in dichloromethane (20 mL) and 5 Mhydrochloric acid in isopropanol (2 mL) was added. The reaction mixturewas stirred at room temperature for 12 h followed by 4 h at 35° C. Thesolvent was evaporated in vacuo. Water (30 mL) was added and the pH wasadjusted to pH 9 using aqueous saturated sodium bicarbonate solution.The aqueous layer was extracted with dichloromethane. The combinedextracts were dried (MgSO₄) and the solvent was evaporated in vacuo.Yield: 790 mg (3.03 mmol, 100%).

248.27-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (790 mg,3.03 mmol), 1,3-dibromopropane (0.4 mL, 3.93 mmol) and triethylamine(0.914 mL, 6.56 mmol) were dissolved in acetonitrile (8 mL) and thereaction mixture heated to 120° C. in the microwave for 2 h. The solventwas evaporated in vacuo. Water (30 mL) and ethyl acetate (40 mL) wereadded. The layers were separated and the aqueous layer extracted withethyl acetate. The combined organic extracts were dried (MgSO₄) and thesolvent evaporated in vacuo. The crude product was purified by flashchromatography (silica gel, dichloromethane, methanol). Yield: 346 mg(1.14 mmol, 37.6%).

248.31-[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methanamine

7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile(340 mg, 1.12 mmol) was dissolved in dry methanol (20 mL) under anitrogen atmosphere. Raney nickel (900 mg, 3.36 mmol) was added undernitrogen and the reaction mixture stirred at room temperature for 48 hunder an atmosphere of hydrogen. Methanol (20 mL) and dichloromethane(30 mL) were added. After stirring at room temperature for 20 minutesthe catalyst was removed by filtration and the solvent evaporated invacuo. Yield: 338 mg (1.10 mmol, 98%).

248.4N-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide

(7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-ylmethanamine(250 mg, 0.816 mmol) and N,N-dimethyl-4-aminopyridine (199 mg, 1.632mmol) were dissolved in dichloromethane (18 mL).1-Methyl-1H-imidazole-4-sulfonyl chloride (147 mg, 0.816 mmol) dissolvedin dichloromethane (2 mL) was added dropwise. The reaction mixture wasstirred at room temperature for 12 h. The reaction mixture was dilutedwith dichloromethane (20 mL) and washed successively with saturatedammonium chloride (3×15 mL) and water (2×10 mL). The organic phase wasdried (MgSO₄) and the solvent was evaporated in vacuo. The crude productwas purified by flash chromatography (silica gel, dichloromethane,methanol). Yield: 64 mg (0.142 mmol, 17%).

ESI-MS [M+H⁺]=451 Calculated for C₂₅H₃₀N₄O₂S=450

The following examples were prepared in analogy to 248:

Example 249N-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamide

ESI-MS [M+H⁺]=413 Calculated for C₂₄H₃₂N₂O₂S=412

Example 250N-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-pyrazole-4-sulfonamide

ESI-MS [M+H⁺]=451 Calculated for C₂₅H₃₀N₄O₂S=450

Example 251N-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-pyrrole-3-sulfonamidetrifluoroacetate

ESI-MS [M+H⁺]=450 Calculated for C₂₆H₃₁N₃O₂S=449

Example 252 Enantiomer 1 ofN-{[7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide

The enantiomer of tert-butyl(1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate describedin example 192 was used as chiral building block for the synthesis.

ESI-MS [M+H⁺]=451 Calculated for C₂₅H₃₀N₄O₂S=450

Example 253 Enantiomer 1 ofN-{[7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}pyridine-2-sulfonamide

The enantiomer of tert-butyl(1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate describedin example 192 was used as chiral building block for the synthesis.

ESI-MS [M+H⁺]=448 Calculated for C₂₆H₂₉N₃O₂S=447

Example 254 Enantiomer 1 ofN-{[7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-pyrazole-4-sulfonamide

The enantiomer of tert-butyl(1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate describedin example 192 was as chiral building block for the synthesis.

ESI-MS [M+H⁺]=451 Calculated for C₂₆H₃₀N₄O₂S=450

Example 255 Enantiomer 1 ofN-{[7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}thiophene-2-sulfonamide

The enantiomer of tert-butyl(1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate describedin example 192 was used as chiral building block for the synthesis.

ESI-MS [M+H⁺]=453 Calculated for C₂₅H₂₈N₂O₂S₂=452

Example 256N-{[7-(Azetidin-1-yl)-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

ESI-MS [M+H⁺]=469 Calculated for C₂₅H₂₉FN₄O₂S=468

Example 257N-{[8-Benzyl-7-(morpholin-4-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide

This compound was prepared in analogy to example 248 using1-bromo-2-(2-bromoethoxy)ethane in place of 1,3-dibromopropane.

ESI-MS [M+H⁺]=481 Calculated for C₂₆H₃₂N₄O₃S=480

The following examples were prepared in analogy to 257:

Example 258N-{[8-Benzyl-7-(morpholin-4-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-pyrazole-4-sulfonamide

ESI-MS [M+H⁺]=481 Calculated for C₂₆H₃₂N₄O₃S=480

Example 259N-{[8-Benzyl-7-(morpholin-4-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-cyclopropylmethanesulfonamide

ESI-MS [M+H⁺]=455 Calculated for C₂₆H₃₄N₂O₃S=454

Example 260N-{[8-Benzyl-7-(morpholin-4-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamide

ESI-MS [M+H⁺]=443 Calculated for C₂₅H₃₄N₂O₃S=442

Example 261N-{[8-Benzyl-7-(morpholin-4-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}cyclobutanesulfonamide

ESI-MS [M+H⁺]=455 Calculated for C₂₆H₃₄N₂O₃S=454

Example 262N-{[8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide

This compound was prepared in analogy to example 248 using1,4-dibromobutane in place of 1,3-dibromopropane.

ESI-MS [M+H⁺]=465 Calculated for C₂₆H₃₂N₄O₂S=464

Example 263N-{[8-Benzyl-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide

N-((7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide(271 mg, 0.66 mmol, cf. 173) was dissolved in dichloromethane (10 mL).Pyridine (0.191 mL, 2.357 mmol) was added. 4-Chlorobutanoyl chloride(0.116 mL, 1.038 mmol) was added dropwise. After 2 hN,N-dimethyl-4-aminopyridine (46 mg, 0.378 mmol) was added and stirringwas continued over night. 1 N sodium hydroxide solution was added andthe mixture extracted with dichloromethane. The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. The crude productwas suspended in dry tetrahydrofuran and a suspension of sodium hydride(60% in oil, 179 mg, washed twice with pentane prior to addition) intetrahydrofuran (3 mL) was added. The reaction mixture was heated to 45°C. for 1 h. Water was added and the mixture was extracted withdichloromethane (3×20 mL). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo. The crude product was purified byflash chromatography (silica gel, dichloromethane, methanol). Yield: 98mg (0.205 mmol, 46%).

ESI-MS [M+H⁺]=479 Calculated for C₂₆H₃₀N₄O₃S=478

Example 264N-{3-[8-(3-Chlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride 264.11-[1-(3-Chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl]pyrrolidine

1-(3-Chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine (6 g,19.88 mmol) was dissolved in acetonitrile (150 mL). 1,4-Dibromobutane(2.61 mL, 21.87 mmol) and triethylamine (6.1 mL, 43.7 mmol) were addedand the reaction mixture heated under reflux for 3 h. The reactionmixture was poured on ice and extracted with dichloromethane. Thecombined organic extracts were successively washed with water and brine,dried (MgSO₄) and the solvent was evaporated in vacuo. The crude product(6.6 g) was used for the next step without further purification.

264.28-(3-Chlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol

1-(1-(3-Chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyrrolidine(6.6 g, 18.54 mmol) was dissolved in dichloromethane (100 mL). A 1 Msolution of bortribromide in dichloromethane (55.6 mL, 55.6 mmol) wasadded dropwise under cooling maintaining the reaction mixture at roomtemperature. The reaction mixture was stirred at room temperature for 2h. The reaction was poured on ice, made alkaline with sodium hydroxide.The aqueous phase was extracted with ethyl acetate and the combinedorganic extracts were washed successively with sodium bicarbonate andbrine. The combined extracts were dried (MgSO₄) and the solvent wasevaporated in vacuo. The crude product (5.5 g) was used for the nextstep without further purification.

264.38-(3-Chlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate

8-(3-Chlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol(5.5 g, 16.09 mmol) was dissolved in dichloromethane (150 mL).1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(6.9 g, 19.31 mmol) was added at 0° C. followed by the addition of asolution of triethylamine (4.48 mL, 32.2 mmol) in dichloromethane (50mL). The reaction mixture was allowed to warm to room temperature andstirring was continued over night. The reaction was poured on ice andextracted with dichloromethane. The combined extracts were washedsuccessively with ammonium chloride solution, water and brine. Theextracts were dried (Na₂SO₄) and the solvent was evaporated in vacuo.The crude product was purified by flash chromatography (silica gel,dichloromethane, methanol). Yield: 6.33 g (13.36 mmol, 83%).

264.4N-{3-[8-(3-Chlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

N-allylpropane-1-sulfonamide (0.238 g, 1.456 mmol) is added to asolution of 9-borabicyclo[3.3.1]nonane (0.185 g, 1.519 mmol) intetrahydrofuran (4 mL). The reaction mixture was stirred for 2 h at roomtemperature.(7R,8S)-8-(3-chlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (0.3 g, 0.633 mmol) dissolved intetrahydrofuran (2 mL), sodium hydroxide (0.063 g, 1.582 mmol in 0.06 mLwater) and palladium tetrakistriphenylphosphine (0.073 g, 0.063 mmol)were added. The reaction mixture was heated under reflux over night. Thereaction mixture was diluted with ethyl acetate and washed with 1 Msodium hydroxide solution. The aqueous phase was extracted two moretimes with ethyl acetate. The combined organic extracts were washed withbrine, dried (MgSO₄) and the solvent was evaporated in vacuo. The crudeproduct was purified by preparative thin-layer-chromatography (silicagel, dichloromethane, methanol). The product was dissolved indichloromethane. Excess 5N hydrochloric acid in ethanol was added. Thesolvent was evaporated and the product dried in vacuo. Yield: 53 mg(0.108 mmol, 17%).

ESI-MS [M+H⁺]=489 Calculated for C₂₇H₃₇ClN₂O₂S=488

The following examples were prepared in analogy to 264:

Example 265 Propane-1-sulfonic acid[3-(8-benzyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yl)propyl]-amidehydrochloride

ESI-MS [M+H⁺]=455 Calculated for C₂₇H₃₈N₂O₂S=454

Example 266N-{3-[8-Benzyl-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamidehydrochloride

ESI-MS [M+H⁺]=467 Calculated for C₂₈H₃₈N₂O₂S=466

Example 267N-(2-{[8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamide267.18-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol

8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-olwas prepared in analogy to8-(3-chlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol(cf. 264).

267.22-{[8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethanamine

2-{[8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethanaminewas prepared in analogy to example 1 and 2 from8-(3-fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol.

267.3N-(2-{[8-(3-fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamide

2-(8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethanamine(50 mg, 0.136 mmol) was dissolved in dichloromethane (2 mL).N,N-Dimethyl-4-aminopyridine (49.7 mg, 0.407 mmol) and1-methyl-1H-pyrrole-3-sulfonyl chloride (24.4 mg, 0.136 mmol) were addedsuccessively. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with dichloromethane and washed withwater. The organic phase was dried (MgSO₄) and the solvent wasevaporated in vacuo. The crude product was purified by flashchromatography (silica gel, dichloromethane, methanol). Yield: 31 mg(0.061 mmol, 45%).

ESI-MS [M+H⁺]=512 Calculated for C₂₈H₃₄FN₃O₃S=511

The following examples were prepared in analogy to 267:

Example 268N-(2-{[7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamide

ESI-MS [M+H⁺]=480 Calculated for C₂₇H₃₃N₃O₃S=479

Example 269 1-Methyl-1H-pyrrole-3-sulfonic acid{2-[7-azetidin-1-yl-8-(3-fluoro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amide

ESI-MS [M+H⁺]=498 Calculated for C₂₇H₃₂FN₃O₃S=497

Example 270 Enantiomer 1 ofN-{1-benzyl-7-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-propionamide

N-{1-Benzyl-7-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-propionamidewas prepared in analogy to example 2 using propionyl chloride in placeof ethyl chloroformate.

Could be separated by chiral chromatography of the final compound or anintermediate.

ESI-MS [M+H⁺]=497 Calculated for C₂₆H₃₂N₄O₄S=496

Example 271N-(2-{[8-(3,5-Difluorobenzyl)-7-(formylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamide271.1 Ethyl[1-(3,5-difluorobenzyl)-7-(2-{[(1-methyl-1H-pyrrol-3-yl)sulfonyl]amino}ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

Ethyl[1-(3,5-difluorobenzyl)-7-(2-{[(1-methyl-1H-pyrrol-3-yl)sulfonyl]amino}ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamatewas prepared in analogy to example 2.

271.2N-(2-{[8-(3,5-Difluorobenzyl)-7-(formylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-pyrrole-3-sulfonamide

Ethyl[1-(3,5-difluorobenzyl)-7-(2-{[(1-methyl-1H-pyrrol-3-yl)sulfonyl]amino}ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate(200 mg, 0.365 mmol) was dissolved in tetrahydrofuran (16 mL). A 1 Msolution of lithium aluminium hydride in tetrahydrofuran (0.73 mL, 0.73mmol) was added dropwise at room temperature. The reaction mixture washeated to 50° C. for 2 h. Under cooling 2N sodium hydroxide solution (3mL) was added dropwise. Water (30 mL) and ethyl acetate (30 mL) wereadded. The aqueous phase was extracted twice with ethyl acetate. Thecombined extracts were dried (MgSO₄) and the solvent was evaporated invacuo. The crude product was purified by flash chromatography (silicagel, dichloromethane, methanol). Yield: 61 mg (0.116 mmol, 32%).

ESI-MS [M+H⁺]=504 Calculated for C₂₅H₂₇F₂N₃O₄S=503

Example 272N-{3-[8-(3,4-Dichlorobenzyl)-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamide272.11-(3,4-Dichlorobenzyl)-7-methoxy-N-(propan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-amine

1-(3,4-Dichlorobenzyl)-7-methoxy-N-(propan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-aminewas isolated as a minor by-product in the recrystallization of1-(3,4-dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-aminehydrochloride from isopropanol.

272.2N-{3-[8-(3,4-Dichlorobenzyl)-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamide

N-{3-[8-(3,4-Dichlorobenzyl)-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidewas prepared in analogy to example 264 using1-(3,4-dichlorobenzyl)-7-methoxy-N-(propan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-aminein place of1-[1-(3-chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl]pyrrolidine.

ESI-MS [M+H⁺]=511 Calculated for C₂₅H₃₂Cl₂N₂O₃S=510

Example 273N-{3-[8-Benzyl-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamidehydrochloride

N-{3-[8-(3,4-Dichlorobenzyl)-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamide(70 mg, 0.137 mmol) was dissolved in methanol (1.5 mL) and palladiumhydroxide (30 mg, 0.214 mmol) was added. The reaction mixture was heatedunder reflux in an atmosphere of hydrogen for 6 h. The catalyst wasremoved by filtration and the crude product was purified by flashchromatography (silica gel, dichloromethane, methanol). The obtainedamine was dissolved in dichloromethane (2 mL) and 5 N hydrochloric acidin isopropanol (0.3 mL) was added. The solvent was evaporated and theproduct dried in vacuo. Yield: 30 mg (0.63 mmol, 46%).

ESI-MS [M+H⁺]=443 Calculated for C₂₆H₃₈N₂O₂S=442

Example 274N-{3-[8-(4-Chlorobenzyl)-7-(diethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamidehydrochloride 274.1N-{3-[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamide

N-{3-[7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamide(cf. 202).

274.2N-{3-[8-(4-Chlorobenzyl)-7-(diethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}-1-cyclopropylmethanesulfonamidehydrochloride

N-(3-(7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl)propyl)-1-cyclopropylmethanesulfonamide(49 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL). Acetic acid(7 μL, 0.11 mmol) was added followed by acetaldehyde (18 μL, 0.322 mmol)in dichloromethane (2 mL) and sodium triacetoxyborohydride (34 mg, 0.16mmol). The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was diluted with dichloromethane (20 mL) and washedwith water (2×10 mL). The organic layer was dried (MgSO₄) and thesolvent was evaporated in vacuo. The crude product was purified by flashchromatography (silica gel, dichloromethane, methanol). The amine wasdissolved in dichloromethane (3 mL) and excess hydrochloric acid inethanol was added. The solvents were evaporated and the product dried invacuo. Yield: 22 mg (0.041 mmol, 38%).

ESI-MS [M+H⁺]=503 Calculated for C₂₈H₃₉ClN₂O₂S=502

Example 275N-{[8-Benzyl-7-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-N-methylpropane-1-sulfonamidetrifluoroacetate

This compound could be prepared in analogy to example 227 usingtert-butyl[(1S,2R)-1-benzyl-7-{[(propylsulfonyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl]carbamatein place of tert-butyl1-(3-fluorobenzyl)-7-(3-(propylsulfonamido)propyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(alkylation of sulfonamide). The tert-butyl carbamate could then bereduced with lithium aluminium hydride as in example 187.

ESI-MS [M+H⁺]=401 Calculated for C₂₃H₃₂N₂O₂S=400

Example 276N-[1-Benzyl-7-{3-[(propylsulfonyl)amino]prop-1-yn-1-yl}-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide

7-Acetamido-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (100 mg, 0.234 mmol; prepared in analogy to8-(3,4-dichlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate, example 29),N-(prop-2-ynyl)propane-1-sulfonamide (75 mg, 0.468 mmol), palladiumtetrakistriphenylphosphine (54 mg, 0.047 mmol), copper(I) iodide (35.6mg, 0.187 mmol) and triethylamine (65 μL, 0.468 mmol) in dioxane (3 mL)were heated under reflux for 16 h. Water (15 mL) was added and themixture extracted with dichloromethane (3×20 mL). The combined organicextracts were dried (MgSO₄) and the solvent was evaporated in vacuo. Thecrude product was purified by flash chromatography (silica gel,dichloromethane, methanol). Yield: 56 mg (0.132 mmol, 57%).

ESI-MS [M+H⁺]=439 Calculated for C₂₅H₃₀N₂O₃S=438

Example 277N-(2-(8-Benzyl-7-(oxetan-3-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-cyclopropylmethanesulfonamide

N-(2-(7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-cyclopropylmethanesulfonamide(50 mg, 0.121 mmol) was dissolved in methanol. Oxetan-3-one (87 mg, 1.21mmol), zinc chloride (66 mg, 0.482 mmol) and sodium cyanoborohydride (23mg, 0.362 mmol) were added at 0° C. The reaction mixture was then heatedto 40° C. for 5 h. Aqueous ammonium chloride solution was added and theaqueous layer was extracted with ethyl acetate. The combined organicextracts were washed with brine, dried (MgSO₄) and concentrated invacuo. The crude product was purified by flash chromatography (silicagel, dichloromethane, methanol). Yield: 3 mg (6.4 μmol, 5%).

ESI-MS [M+H⁺]=471 Calculated for C₂₆H₃₄N₂O₄S=470

Example 278 Propane-1-sulfonic acid(8-benzyl-7-cyclopropylamino-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-amidehydrochloride

N-((7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)propane-1-sulfonamide(51 mg, 0.137 mmol), (1-ethoxycyclopropoxy)trimethylsilane (26 mg, 0.151mmol), acetic acid (0.078 mL, 1.37 mmol), sodium cyanoborohydride (26mg, 0.411 mmol) and molecular sieve (50 mg) in methanol (1.5 mL) wereheated in the microwave at 100° C. for 25 min. The solvent wasevaporated and the crude product purified by flash chromatography(silica gel, dichloromethane, methanol) and converted into the hydrochloride. Yield: 18 mg (0.04 mmol, 29%).

ESI-MS [M+H⁺]=413 Calculated for C₂₄H₃₂N₂O₂S=412

Example 279(1-(4-Chloro-benzyl)-7-{2-[methyl-(propane-1-sulfonyl)-amino]-ethoxy}-1,2,3,4-tetrahydronaphthalen-2-yl)-carbamicacid ethyl ester 279.1 Propane-1-sulfonic acid cyclopropyl amide

To a solution of cyclopropylamine (1.2 ml, 17.5 mmol) in 100 ml CH₂Cl₂and DMAP (2.4 g, 17.5 mmol) was added dropwise a solution ofpropane-1-sulfonyl chloride (2.3 ml, 19.2 mmol) in 50 ml CH₂Cl₂. Theresulting mixture was stirred at room temperature over night and dilutedwith 50 ml of CH₂Cl₂. The mixture was extracted subsequently with water,1 M HCl, and brine, tried over Na₂SO₄, filtered and the solventevaporated to obtain 2.8 g of product (oil) which was used in the nextstep without further purification.

279.2 Acetic acid 2-[cyclopropyl-(propane-1-sulfonyl)-amino]-ethyl ester

A mixture of propane-1-sulfonic acid cyclopropyl amide (1.3 g, 8 mmol),K2CO3 (2.4 g, 14.4 mmol) and acetic acid 2-bromo-ethyl ester (9.5 g, 16mmol) mmol) in 10 ml acetone was heated for 6 h to 120° C. in themicrowave (Biotage). After cooling the mixture was filtered and thesolvent evaporated to obtain 1.7 g of product as an oil which was usedwithout further purification in the next step.

279.3 Propane-1-sulfonic acid cyclopropyl-(2-hydroxy-ethyl)-amide

A mixture of acetic acid 2-[cyclopropyl-(propane-1-sulfonyl)-amino]ethylester (1.7 g, 6.8 mmol) and KOH (0.57 g, 10.2 mmol) in 30 ml Methanolwas stirred over night at room temperature. The solvent was evaporatedthe residue dissolved in ethyl acetate and subsequently extracted withwater and 1 M KOH, dried over Na₂SO₄ and the solvent evaporated toobtain 0.46 g of product which was used purified by chromatography(253.5 mg of colorless oil)

279.4 Propane-1-sulfonic acid2-[cyclopropyl-(propane-1-sulfonyl)-amino]ethyl ester

To a solution of propane-1-sulfonic acidcyclopropyl-(2-hydroxy-ethyl)-amide (150 mg, 0.8 mmol) in CH₂Cl₂ andDMAP (97 mg, 0.8 mmol) was added dropwise a solution ofpropane-1-sulfonyl chloride (97 mg, 0.8 mmol) in CH₂Cl₂. The resultingmixture was stirred at room temperature over night, diluted with 50 mlof CH₂Cl₂, extracted subsequently with water, 1 M HCl, and brine, triedover Na₂SO₄, filtered and the solvent evaporated to obtain 197.5 mg ofproduct which was used in the next step without further purification.

279.51-(3-Chloro-benzyl)-7-{2-[cyclopropyl-(propane-1-sulfonyl)-amino]-ethoxy}-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamicacid ethyl ester

Prepared in one step from ethyl1-(3-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(prepared in analogy to example 1d) and propane-1-sulfonic acid2-[cyclopropyl-(propane-1-sulfonyl)-amino]ethyl ester in analogy toexample 76.

ESI-MS [M+H⁺]=549 Calculated for C₂₈H₃₇ClN₂O₅S=548

Example 2801-Benzyl-7-{2-[cyclopropyl-(propane-1-sulfonyl)-amino]-ethoxy}-1,2,3,4-tetrahydronaphthalen-2-yl)-carbamicacid ethyl ester

Prepared in one step from ethyl1-benzyl-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (preparedin analogy to example 1d) and propane-1-sulfonic acid2-[cyclopropyl-(propane-1-sulfonyl)-amino]-ethyl ester in analogy toexample 76.

ESI-MS [M+H⁺]=515 Calculated for C₂₈H₃₈N₂O₅S=514

Example 281 Propane-1-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-cyclopropyl-amidehydrochloride

Prepared in one step from1-(3-Chloro-benzyl)-7-{2-[cyclopropyl-(propane-1-sulfonyl)amino]-ethoxy}-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamicacid ethyl ester (example 279) example in analogy to example 3.

ESI-MS [M+H⁺]=477 Calculated for C₂₅H₃₃ClN₂O₃S=476

Example 282 Propane-1-sulfonic acid[2-(7-amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)ethyl]-cyclopropyl-amidehydrochloride

Prepared in one step from1-Benzyl-7-{2-[cyclopropyl-(propane-1-sulfonyl)-amino]-ethoxy}-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamicacid ethyl ester (example 280) in analogy to example 3.

ESI-MS [M+H⁺]=443 Calculated for C₂₅H₃₄N₂O₃S=442

Example 2831-(3-Chloro-benzyl)-7-[1-(propane-1-sulfonyl)-azetidin-3-yl]-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride 283.13-[8-(3-Chloro-benzyl)-7-ethoxycarbonylamino-5,6,7,8-tetrahydro-naphthalen-2-yl]-azetidine-1-carboxylicacid tert-butyl ester

A suspension of zinc powder (152 mg, 2.3 mmol) in 1 ml of DMA in a dryflask was heated under N₂ to 65-70° C. A mixture of TMS-Cl (28 mg, 0.26mmol) and 1,2-dibromoethane (49 mg, 0.26 mmol) was added dropwise,stirred for 30 min, followed by slow (15 min) addition of3-iodo-azetidine-1-carboxylic acid tert-butyl ester (510 mg, 1.8 mmol)in 1 ml DMA. The reaction was cooled slowly (3 h) to room temperature,added to a mixture of8-(3,4-chlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (633 mg, 1.3 mmol, prepared in analogy toexample 29), CuI (74 mg, 0.39 mmol) and PdCl₂(dppf) (63 mg, 0.08 mmol)in 4 ml DMA preheated to 70° C. and stirred for 7 h at 70° C. Water andMTB (1:1 20 ml) were added and the resulting mixture filtered. Theorganic layer was separated, dried (Na₂SO₄) and the solvent evaporated.Purification by chromatography afforded 560 mg of product (white foam).

283.21-(3-Chloro-benzyl)-7-[1-(propane-1-sulfonyl)-azetidin-3-yl]-1,2,3,4-tetrahydronaphthalen-2-ylaminehydrochloride

Prepared in three steps from3-[8-(3-chloro-benzyl)-7-ethoxycarbonylamino-5,6,7,8-tetrahydro-naphthalen-2-yl]-azetidine-1-carboxylicacid tert-butyl ester in analogy to example 46/47.

Cleavage of Boc-group was done in formic acid.

ESI-MS [M+H⁺]=433 Calculated for C₂₃H₂₉ClN₂O₂S=432

Example 2841-Benzyl-7-[1-(propane-1-sulfonyl)-azetidin-3-yl]-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride

Prepared in analogy to example 283.

ESI-MS [M+H⁺]=399 Calculated for C₂₃H₃₀N₂O₂S=398

Example 285{1-(3-Chloro-benzyl)-7-[1-(propane-1-sulfonyl)-azetidin-3-ylmethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester 285.1 1-(Propane-1-sulfonyl)-azetidine-3-carboxylicacid methyl ester

Prepared by standard procedure from azetidine-3-carboxylic acid methylester and propane-1-sulfonyl chloride (e.g. example 279).

285.2 [1-(Propane-1-sulfonyl)-azetidin-3-yl]-methanol

Prepared by reduction of 1-(propane-1-sulfonyl)-azetidine-3-carboxylicacid methyl with LiAlH4 in THF at room temperature to 50° C. (e.g.example 300).

285.3 Methanesulfonic acid 1-(propane-1-sulfonyl)-azetidin-3-ylmethylester

Prepared by standard procedure from[1-(propane-1-sulfonyl)-azetidin-3-yl]-methanol and methan-1-sulfonylchloride (e.g. example 40)

285.4{1-(3-Chloro-benzyl)-7-[1-(propane-1-sulfonyl)-azetidin-3-ylmethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester

Prepared from1-(3-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamateand methanesulfonic acid 1-(propane-1-sulfonyl)-azetidin-3-ylmethylester in analogy to example 315.

ESI-MS [M+H⁺]=536 Calculated for C₂₇H₃₅ClN₂O₅S=535

Example 2861-(3-Chloro-benzyl)-7-[1-(propane-1-sulfonyl)-azetidin-3-ylmethoxy]-1,2,3,4-tetrahydronaphthalen-2-ylaminehydrochloride

Prepared from{1-(3-chloro-benzyl)-7-[1-(propane-1-sulfonyl)-azetidin-3-ylmethoxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester in analogy to example 3.

ESI-MS [M+H⁺]=463 Calculated for C₂₄H₃₁ClN₂O₃S=462

Example 287[1-(3-Chloro-benzyl)-7-(2-cyclopropylmethanesulfonylamino-ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester

Prepared in analogy to example 3.

ESI-MS [M+H⁺]=521 Calculated for C₂₆H₃₃ClN₂O₅S=520

Example 288N-{2-[7-Amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-methanesulfonamidehydrochloride

Prepared from[1-(3-chloro-benzyl)-7-(2-cyclopropylmethanesulfonylamino-ethoxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 3.

ESI-MS [M+H⁺]=449 Calculated for C₂₃H₂₉ClN₂O₃S=448

Example 289[1-(3-Chloro-benzyl)-7-(1-cyclopropylmethanesulfonyl-azetidin-3-ylmethoxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester

Prepared from1-(3-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamateand methanesulfonic acid Methanesulfonic acid1-cyclopropylmethanesulfonyl-azetidin-3-yl methylester (prepared inanalogy to example 285) in analogy to example 315.

ESI-MS [M+H⁺]=547 Calculated for C₂₈H₃₅ClN₂O₅S=546

Example 290{1-(3-Chloro-benzyl)-7-[2-(cyclopropylmethanesulfonyl-methyl-amino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared from[1-(3-chloro-benzyl)-7-(2-cyclopropylmethanesulfonylamino-ethoxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 45.

ESI-MS [M+H⁺]=535 Calculated for C₂₇H₃₅ClN₂O₅S=534

Example 291N-{2-[7-Amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-N-methyl-methanesulfonamide

{1-(3-Chloro-benzyl)-7-[2-(cyclopropylmethanesulfonyl-methyl-amino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester in analogy to example 3.

ESI-MS [M+H⁺]=463 Calculated for C₂₄H₃₁ClN₂O₃S=462

Example 2921-Benzyl-7-[1-(propane-1-sulfonyl)-azetidin-3-ylmethoxy]-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride

Prepared in analogy to example 46.

ESI-MS [M+H⁺]=429 Calculated for C₂₄H₃₁ClN₂O₃S=428

Example 293 Propane-1-sulfonic acid{2-[7-amino-8-(2-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to example 3.

ESI-MS [M+H⁺]=437 Calculated for C₂₂H₂₉ClN₂O₃S=436

Example 294 Cyclopropanesulfonic acid{2-[7-amino-8-(2-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to example 3.

ESI-MS [M+H⁺]=435 Calculated for C₂₂H₂₇ClN₂O₃S=434

Example 295N-{2-[7-Amino-8-(2-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-methanesulfonamidehydrochloride

Prepared in analogy to example 3.

ESI-MS [M+H⁺]=449 Calculated for C₂₃H₂₉ClN₂O₃S=448

Example 296N-{3-[7-Amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-propyl}-C-cyclopropyl-methanesulfonamidehydrochloride 296.1[7-(3-tert-Butoxycarbonylamino-propyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester

A solution of tert-butyl allylcarbamate (297 mg, 1.9 mmol) in dry THFunder nitrogen was added dropwise at 0° C. to 9-BBN dissolved in THF(0.5 M, 2.3 ml, 1.2 mmol) and stirred for 4 h. This mixture wassubsequently treated with8-(3,4-chlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (250 mg, 0.5 mmol), palladium(11)acetate (11.5mg, 0.05 mmol), triphenylphosphine (27 mg, 0.1 mmol) and cesiumcarbonate (333 mg, 1 mmol) after which the mixture was heated to refluxfor 2 h.

The solvent was evaporated the residue dissolved in ethylacetate,extracted with water, dried (Na₂SO₄). Evaporation of solvent gave 0.51 gof a brown oil which was treated with diisopropyl ether to afford 91 mgof a brownish powder.

296.2N-{3-[7-Amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-propyl}-C-cyclopropyl-methanesulfonamidehydrochloride

Prepared from[7-(3-tert-butoxycarbonylamino-propyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 3.

ESI-MS [M+H⁺]=447 Calculated for C₂₄H₃₁ClN₂O₂S=446

Example 297 Propane-1-sulfonic acid{3-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-propyl}-amidehydrochloride

Prepared in analogy to example 296.

ESI-MS [M+H⁺]=435 Calculated for C₂₃H₃₁ClN₂O₂S=434

Example 298{1-(2-Chloro-benzyl)-7-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in analogy to example 3.

ESI-MS [M+H⁺]=547 Calculated for C₂₆H₃₁ClN₄O₅S=546

Example 299{1-(2-Chloro-benzyl)-7-[2-(1-methyl-1H-pyrazole-4-sulfonylamino)-ethoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-carbamicacid ethyl ester

Prepared in analogy to example 3.

ESI-MS [M+H⁺]=547 Calculated for C₂₆H₃₁ClN₄O₅S=546

Example 300N-{2-[8-(3-Chloro-benzyl)-7-methylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-methanesulfonamidehydrochloride

A solution of LiAlH₄ in THF (1 M, 1.5 ml, 1.5 mmol) was added dropwiseto[1-(3-chlorobenzyl)-7-(2-cyclopropylmethanesulfonylamino-ethoxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester (523 mg, 1 mmol, example 287) dissolved in 100 ml ofdry THF. The mixture was heated to reflux for 1 h, treated with 2N NaOH,and extracted with CH₂Cl₂. The organic layer was extracted with sat.NaHCO₃ and brine, dried (Na₂SO₄) filtered and the solvent evaporated.Purification by chromatography afforded 324 mg of product as colorlessoil which was transformed to the hydrochloride in a mixture of HCl inisopropanol. (325 mg, white powder)

ESI-MS [M+H⁺]=463 Calculated for C₂₄H₃₁ClN₂O₃S=462

Example 301 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[7-amino-8-(2-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to example 3.

ESI-MS [M+H⁺]=475 Calculated for C₂₃H₂₇ClN₄O₃S=474

Example 302 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[8-(2-chloro-benzyl)-7-methylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to example 3/300.

ESI-MS [M+H⁺]=489 Calculated for C₂₄H₂₉ClN₄O₃S=488

Example 303 1-Methyl-1H-imidazole-4-sulfonic acid{2-[8-(2-chloro-benzyl)-7-methylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to example 3/300.

ESI-MS [M+H⁺]=489 Calculated for C₂₄H₂₉ClN₄O₃S=488

Example 304 Propane-1-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-ethyl}-amidehydrochloride 304.1[7-(2-Benzyloxycarbonylamino-ethyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester

A mixture of potassium (2-(benzyloxycarbonylamino)ethyl)trifluoroborate(1,130 g, 3.96 mmol), cesium carbonate (2.58 g, 7.93 mmol),8-(3-chlorobenzyl)-7-(ethoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (1.3 g, 2.64 mmol), Pd(OAc)₂ (0.030 g, 0.132mmol) and 2-dicyclohexyphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (0.130g, 0.264 mmol) under N₂ in toluene/water 3:1 (15 ml) was heated torefluxed for 13 h. The reaction was filtered, the solvent evaporated andthe residue purified by chromatography to afford 1.04 g of product ascolorless oil.

304.2[7-(2-Amino-ethyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester

To[7-(2-benzyloxycarbonylamino-ethyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester (500 mg, 0.960 mmol) was added at room temperature 8 mlof 33% HBr in acetic acid. After 2 h the mixture was diluted withCH₂Cl₂, washed twice with NaHCO₃, dried and filtered. The solvent wasevaporated to obtain the product as a yellow oil (392 mg), which wasused without further purification.

304.3 Propane-1-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-ethyl}-amidehydrochloride

Prepared from[7-(2-amino-ethyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester in analogy to example 3.

ESI-MS [M+H⁺]=421 Calculated for C₂₂H₂₉ClN₂O₂S=420

Example 305 1-Methyl-1H-imidazole-4-sulfonic acid{2-[7-amino-8-(2-chloro-benzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to example 3.

ESI-MS [M+H⁺]=475 Calculated for C₂₃H₂₇ClN₄O₃S=474

Example 306N-[1-(3-Chloro-benzyl)-7-(2-cyclopropylmethanesulfonylamino-ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-acetamide

Prepared in analogy to example 214.

ESI-MS [M+H⁺]=491 Calculated for C₂₅H₃₁ClN₂O₄S=490

Example 307N-{2-[8-(3-Chloro-benzyl)-7-ethylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-methanesulfonamidehydrochloride

Prepared in analogy to example 300.

ESI-MS [M+H⁺]=477 Calculated for C₂₅H₃₃ClN₂O₃8=476

Example 308 Propane-1-sulfonic acid{3-[8-(3-chloro-benzyl)-7-methylamino-5,6,7,8-tetrahydronaphthalen-2-yl]-propyl}-amidehydrochloride

Prepared in analogy to examples 297/300.

ESI-MS [M+H⁺]=449 Calculated for C₂₄H₃₃ClN₂O₂8=448

Example 309 Propane-1-sulfonic acid{2-[8-(3-chloro-benzyl)-7-methylamino-5,6,7,8-tetrahydronaphthalen-2-yl]-ethyl}-amide

Prepared in analogy to examples 304/300.

ESI-MS [M+H⁺]=435 Calculated for C₂₃H₃₁ClN₂O₂S=434

Example 310N-{2-[7-Amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-ethyl}-C-cyclopropyl-methanesulfonamidehydrochloride

Prepared in analogy to example 304.

ESI-MS [M+H⁺]=433 Calculated for C₂₃H₂₉ClN₂O₂S=432

Example 311 Propane-1-sulfonic acid{2-[8-(2-fluoro-benzyl)-7-methylamino-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to examples 3/300.

ESI-MS [M+H⁺]=435 Calculated for C₂₃H₃₁FN₂O₃=434

Example 312C-Cyclopropyl-N-{2-[8-(2-fluoro-benzyl)-7-methylamino-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-methanesulfonamidehydrochloride

Prepared in analogy to examples 3/300.

ESI-MS [M+H⁺]=447 Calculated for C₂₄H₃₁FN₂O₃S=446

Example 313 1-Methyl-1H-imidazole-4-sulfonic acid{2-[8-(3-chloro-benzyl)-7-methylamino-5,6,7,8-tetrahydro-naphthalen-2-yl]-ethyl}-amide

Prepared in analogy to examples 304/300.

ESI-MS [M+H⁺]=473 Calculated for C₂₄H₂₉ClN₄O₂S=472

Example 314 Propane-1-sulfonic acid[2-(8-cyclohexylmethyl-7-methylamino-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-amidetrifluoroacetate

Prepared in analogy to examples 3/300.

ESI-MS [M+H⁺]=423 Calculated for C₂₃H₃₈N₂O₃S=422

Example 315 1-Methyl-1H-imidazole-4-sulfonic acid{2-[8-(2-chloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride 315.1 1-Methyl-1H-imidazole-4-sulfonic acid{2-[8-(2-chloro-benzyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amide

Prepared in analogy to example 263.

315.2 1-Methyl-1H-imidazole-4-sulfonic acid{2-[8-(2-chloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared from compound of previous step by reduction with LiAlH₄ inanalogy to 300.

ESI-MS [M+H⁺]=529 Calculated for C₂₇H₃₃ClN₄O₃S=528

Example 316 1,2-Dimethyl-1H-imidazole-4-sulfonic acid{2-[7-amino-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to example 3.

ESI-MS [M+H⁺]=489 Calculated for C₂₄H₂₉ClN₄O₃S=488

Example 317N-{2-[8-(3-Chloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-methanesulfonamidehydrochloride

Prepared in analogy to examples 264/88.

ESI-MS [M+H⁺]=503 Calculated for C₂₇H₃₅ClN₂O₃S=502

Example 318 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[8-(3-chloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to examples 264/88.

ESI-MS [M+H⁺]=529 Calculated for C₂₇H₃₃ClN₄O₃S=528

Example 319 1-Methyl-1H-imidazole-4-sulfonic acid{2-[8-(3-chloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to examples 264/88.

ESI-MS [M+H⁺]=529 Calculated for C₂₇H₃₃ClN₄O₃S=528

Example 320N-{2-[7-Azetidin-1-yl-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-methanesulfonamide320.11-[1-(3-Chloro-benzyl)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-azetidine

Prepared in analogy to example 264 using 1,3-dibromopropane instead of1,4-dibromobutane.

320.2N-{2-[7-Azetidin-1-yl-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-C-cyclopropyl-methanesulfonamide

Prepared from compound of previous step in analogy to example 88.

ESI-MS [M+H⁺]=489 Calculated for C₂₆H₃₃ClN₂O₃S=488

Example 321 1-Methyl-1H-imidazole-4-sulfonic acid{2-[7-azetidin-1-yl-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to example 320.

ESI-MS [M+H⁺]=515 Calculated for C₂₆H₃₁ClN₄O₃S=514

Example 322 1-Methyl-1H-pyrazole-4-sulfonic acid{2-[7-azetidin-1-yl-8-(3-chloro-benzyl)-5,6,7,8-tetrahydro-naphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to example 320.

ESI-MS [M+H⁺]=515 Calculated for C₂₆H₃₁ClN₄O₃S=514

Example 323 Propane-1-sulfonic acid{2-[8-(3-chloro-benzyl)-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-2-yloxy]-ethyl}-amidehydrochloride

Prepared in analogy to examples 264/88.

ESI-MS [M+H⁺]=491 Calculated for C₂₆H₃₅ClN₂O₃S=490

Example 324 1-Methyl-1H-pyrazole-4-sulfonic acid[2-(7-azetidin-1-yl-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-ethyl]-amidehydrochloride

Prepared in analogy to example 320.

ESI-MS [M+H⁺]=481 Calculated for C₂₆H₃₂N₄O₃S=480

Example 3251-Benzyl-7-[2-(propane-1-sulfonyl)-ethyl]-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride 325.1[1-(3-Chloro-benzyl)-7-vinyl-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester

Synthesis performed in analogy to: Organic Letters; 2002, Vol 4; p.107-109.

A solution of potassium trifluoro(vinyl)borate (1,000 g, 7.46 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (0.102 g, 0.124 mmol),8-(3-chlorobenzyl)-7-(ethoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (3.06 g, 6.22 mmol) and triethylamine (0.867ml, 6.22 mmol) in 100 ml n-BuOH was stirred under N₂ at 85-90° C. for 4h and then cooled to room temperature.

Water was added, followed by extraction with ether. The etherealsolution was washed with brine, dried, filtered and evaporated to obtaina brown oil. Chromatography afforded 1.55 g of product as a pale yellowsolid.

325.2[1-(3-Chloro-benzyl)-7-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester

BH₃.DMS (1 M in THF, 0.838 ml, 0.838 mmol) was added a solution of ethyl1-(3-chlorobenzyl)-7-vinyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(1.55 g, 4.19 mmol) in 20 ml dry THF. The reaction was stirred at 60° C.for 1 h and cooled to room temperature. Some water was added to destroythe excess of borane complex and the resulting mixture refluxed for 1 hwith 30% H₂O₂ (8.56 ml, 84 mmol) and 2N NaOH (9.74 ml, 19.49 mmol). Thereaction mixture was extracted with CH₂Cl₂, washed with water and brine,dried, filtered and the solvent evaporated to obtain a pale brown solid(1.7 g), which was purified by chromatography to afford 854 mg ofproduct as a white solid.

325.3[7-(2-Bromo-ethyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester

To a solution of[1-(3-chloro-benzyl)-7-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester (554 mg, 1.428 mmol) in 15 ml dry CH₂Cl₂ cooled to 0°C. was added triphenylphosphine (562 mg, 2.142 mmol) and carbontetrabromide (0.208 ml, 2.142 mmol). The mixture was stirred for 1 h,after which solvents were evaporated. The residue was purified bychromatography to obtain 277 mg of product as a white solid.

325.4[1-(3-Chloro-benzyl)-7-(2-propylsulfanyl-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester

To a suspension of NaH (4.73 mg, 0.177 mmol) in 3 ml dry DMF under N₂was added 1-propanthiol (0.012 ml, 0.133 mmol, dissolved in 1 ml dryDMF). The reaction was stirred at room temperature for 2 h, followed byaddition of triethylamine (0.019 ml, 0.133 mmol) and ethyl7-(2-bromoethyl)-1-(3-chlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(40 mg, 0.089 mmol, dissolved in 2 ml dry DMF). The mixture was stirredat room temperature over night, the solvent evaporated, the residuere-dissolved in ethyl acetate, washed with water, citric acid, NaHCO₃and brine and filtered. The solvent was evaporated to obtain 31 mg of anoff white solid which was used without further purification.

325.5{1-(3-Chloro-benzyl)-7-[2-(propane-1-sulfonyl)-ethyl]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamicacid ethyl ester

To a cooled mixture (0° C.) of ethyl1-(3-chlorobenzyl)-7-(2-(propylthio)ethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(31.4 mg, 0.070 mmol) in 2 ml ethyl acetate was added m-CPBA (33.4 mg,0.155 mmol). The reaction was stirred for 2 h allowing warming up toroom temperature. The mixture was diluted with ethyl acetate, washedwith NaHCO₃, water and brine, dried, filtered and the solvent evaporatedto obtain a white solid, which was purified by chromatography (27 mg).

325.6[1-Benzyl-7-(2-propylsulfanyl-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamicacid ethyl ester

Ethyl1-(3-chlorobenzyl)-7-(2-(propylsulfonyl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate(27.1 mg, 0.057 mmol) and ammonium formiate (71.5 mg, 1.134 mmol) weredissolved in 5 ml MeOH. Pd/C (0.845 mg, 7.94 μmol) was added and stirredat 80° C. for 4 h. The mixture was filtered, the solvent evaporated, theresidue re-dissolved in ethyl acetate, which was subsequently washedwith water, NaHCO₃ and brine, dried, filtered. Solvent was evaporated toobtain white solid which was purified by chromatography affording 12.7mg of product as a white solid.

325.71-Benzyl-7-[2-(propane-1-sulfonyl)-ethyl]-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride

Prepared in analogy to example 3[1-Benzyl-7-(2-propylsulfanyl-ethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamicacid ethyl ester.

ESI-MS [M+H⁺]=372 Calculated for C₂₂H₂₉NO₂S=371

Example 3261-(3-Chloro-benzyl)-7-[2-(propane-1-sulfonyl)-ethyl]-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride

Prepared in analogy to example 325 leaving out the de-chlorination step.

ESI-MS [M+H⁺]=406 Calculated for C₂₂H₂₉ClNO₂S=405

Biological Testing

1. [³H]-Glycine Uptake into Recombinant CHO Cells Expressing HumanGlyT1:

Human GlyT1c expressing recombinant hGlyT1c_(—)5_CHO cells were platedat 20,000 cells per well in 96 well Cytostar-T scintillation microplates(Amersham Biosciences) and cultured to sub-confluency for 24 h. Forglycine uptake assays the culture medium was aspirated and the cellswere washed once with 100 μl HBSS (Gibco BRL, #14025-050) with 5 mML-Alanine (Merck #1007). 80 μl HBSS buffer were added, followed by 10 μlinhibitor or vehicle (10% DMSO) and 10 μl [³H]-glycine (TRK71, AmershamBiosciences) to a final concentration of 200 nM for initiation ofglycine uptake. The plates were placed in a Wallac Microbeta(PerkinElmer) and continuously counted by solid phase scintillationspectrometry during up to 3 hours. Nonspecific uptake was determined inthe presence of 10 μM Org24598. IC₅₀ calculations were made byfour-parametric logistic nonlinear regression analysis (GraphPad Prism)using determinations within the range of linear increase of [³H]-glycineincorporation between 60 and 120 min.

2. Radioligand Binding Assays Using Recombinant CHO Cell MembranesExpressing Human GlyT1:

Radioligand binding to human GlyT1c transporter-expressing membranes wascarried out as described in Mezler et al., Molecular Pharmacology74:1705-1715, 2008.

The following results were obtained with the compounds disclosed in theexamples:

TABLE 1 Glycine uptake radioligand binding Example IC₅₀ [μmol] K_(iapp)[μmol] 1 ≦1000 ≦10 2 ≦1 ≦0.1 3 ≦0.01 ≦0.01 4 ≦0.01 ≦0.01 5 ≦1 ≦1 6 ≦1≦0.1 7 ≦10 ≦10 8 ≦0.1 ≦0.1 9 ≦1 ≦1 10 ≦100 ≦10 11 ≦1 ≦0.1 12 ≦100 ≧10 13≦1000 ≦100 14 ≦1000 ≦100 15 ≦1 ≦1 16 ≦10 ≦10 17 ≦10 ≦1 18 ≦0.1 ≦0.01 19≦100 ≦10 20 ≦0.1 ≦0.01 21 ≦1000 ≦100 22 ≦1000 ≦10 23 ≦100 ≦10 24 ≦10≦0.1 25 ≦1 ≦0.1 26 ≦1000 ≦10 27 ≦0.01 ≦0.01 28 ≦0.01 ≦0.01 29 ≦100 ≦1030 ≦100 ≦100 31 ≦1 ≦0.1 32 ≦100 ≦10 33 ≦1 ≦1 34 ≦1000 ≦10 35 ≦100 ≧10036 ≦10 ≦100 37 ≦100 ≦10 38 ≦100 ≦100 39 ≦1000 ≦10 40 ≦100 ≦10 41 ≦100≦10 42 ≦0.1 ≦0.1 43 ≦1 ≦0.1 44 ≦0.1 ≦0.1 45 ≦0.1 ≦0.1 46 ≦1 ≦1 47 ≦0.01≦0.01 48 ≦0.01 ≦0.01 49 ≦100 ≦100 50 ≦10 ≦1 51 ≦1000 ≦100 52 ≦10 ≦10 53≦1000 ≦10 54 ≧100 ≦10 55 ≦0.1 ≦0.01 56 ≦1 ≦0.1 57 ≦10 ≦1 58 ≦10 ≦1 59≦10 ≦1 60 ≧100 ≦10 61 ≦1000 ≦10 62 ≦1000 ≦10 63 ≧100 ≦10 64 ≦1000 ≦10 65≦100 ≧10 66 ≦1 ≦0.1 67 ≦1 ≦0.1 68 ≦10 ≦1 69 ≦10 ≦1 70 ≦1 ≦0.1 71 ≦0.1≦0.01 72 ≦10 ≦10 73 ≦10 ≦1 74 ≦100 ≧10 75 ≦10 ≦1 76 ≦1000 ≦100 77 ≦1≦0.1 78 ≦10 ≦10 79 ≦1 ≦0.1 80 ≦1 ≦1 81 ≧1000 ≦10 82 ≦1 ≦0.1 83 ≦10 ≦1 84≦10 ≦10 85 — ≦1 86 — ≦10 87 — ≦10 88 — ≦0.1 89 — ≦0.1 90 — ≦1 91 — ≦0.192 — — 93 — ≦1 94 — ≦0.1 95 — ≦0.01 967 — ≦1 98 — ≦1 99 — ≦0.1 100 — ≦1100 — ≦10 101 — ≦0.1 102 — ≦1 103 — ≦10 104 — ≦1 105 — ≦0.1 106 — ≦1 107— ≦0.1 108 — ≦0.01 109 — ≦0.1 110 — ≦1 111 — ≦0.1 112 — ≦0.1 113 — ≦0.1114 — ≦1 115 — — 116 — ≦0.01 117 — ≦0.01 118 — ≦0.1 119 — ≦0.01 120 —≦0.1 121 — ≦0.01 122 — ≦10 123 — ≦10 124 — ≦1 125 — ≦1 126 — ≦0.01 127 —≦0.1 128 — ≦0.1 129 — ≦0.01 130 — ≦0.01 131 — ≦0.1 132 — ≦0.1 133 — ≦0.1134 — ≦1 135 — ≦0.1 136 — ≦0.1 137 — ≦0.01 138 — ≦0.01 139 — ≦0.01 140 —≦0.01 141 — ≦0.01 142 — ≦0.1 143 — ≦0.01 144 — ≦1 145 — ≦0.01 146 —≦0.01 147 — ≦0.1 148 — ≦0.1 149 — ≦0.1 150 — ≦0.01 151 — ≦0.01 152 —≦0.01 153 — ≦0.1 154 — ≦0.1 155 — ≦1 156 — ≦1 157 — ≦0.1 158 — ≦0.01 159— ≦0.1 160 — ≦0.01 161 — ≦0.01 162 — ≦0.01 163 — ≦0.01 164 — ≦0.01 165 —≦0.01 166 — ≦0.1 167 — ≦10 168 — ≦10 169 — ≦0.01 170 — >10 171 — ≦0.1172 — ≦0.01 173 — ≦0.01 174 — ≦1 175 — ≦1 176 — ≦0.1 177 — ≦0.01 178 —≦0.01 179 — ≦1 180 — ≦0.01 181 — ≦0.1 182 — ≦0.1 183 — ≦1 184 — ≦0.1 185— ≦1 186 — ≦1 187 — ≦0.01 188 — ≦0.1 189 — ≦10 190 — ≦0.01 191 — ≦1 192— — 193 — ≦0.01 194 — — 195 — — 196 — ≦10 197 — ≦10 198 — ≦0.1 199 —≦0.1 200 — ≦0.1 201 — ≦0.1 202 — ≦0.1 203 — ≦0.01 204 — ≦0.1 205 — ≦0.1206 — ≦0.1 207 — ≦0.1 208 — ≦0.1 209 — ≦0.1 210 — ≦0.1 211 — ≦1 212 — ≦1213 — ≦0.1 214 — ≦10 215 — ≦10 216 — ≦10 217 — ≦10 218 — ≦10 219 — ≦0.1220 — ≦1 221 — ≦0.1 222 — ≦1 223 — ≦0.1 224 — ≦0.1 225 — ≦0.1 226 — ≦0.1227 — ≦0.1 228 — ≦0.1 229 — ≦1 230 — ≦0.01 231 — ≦0.01 232 — ≦0.1 233 —≦0.1 234 — ≦0.1 235 — ≦0.01 236 — ≦1 237 — ≦10 238 — ≦0.01 239 — ≦1 240— ≦0.01 241 — ≦0.1 242 — ≦0.01 243 — ≦0.01 244 — ≦0.01 245 — ≦1 246 —≦0.01 247 — ≦0.01 248 — ≦0.01 249 — ≦0.1 250 — ≦0.01 251 — ≦0.1 252 —≦0.01 253 — ≦1 254 — ≦0.01 255 — ≦1 256 — ≦0.1 257 — ≦0.1 258 — ≦0.1 259— ≦1 260 — ≦1 261 — ≦1 262 — ≦0.1 263 — ≦1 264 — ≦1 265 — ≦1 266 — ≦1267 — ≦0.1 268 — ≦0.01 269 — ≦0.01 270 — ≦0.1 271 — ≦0.1 272 — ≦0.1 273— ≦1 274 — ≦0.1 275 — ≦0.1 276 — ≦10 277 — 278 — 279 — ≦10 280 — ≦10 281— ≦0.1 282 — ≦0.1 283 — ≦1 284 — ≦1 285 — ≦10 286 — ≦10 287 — ≦10 288 —≦0.01 289 — >10 290 — ≦10 291 — ≦0.01 292 — ≦1 293 — ≦1 294 — ≦10 295 —≦1 296 — ≦0.1 297 — ≦0.1 298 — ≦10 299 — >10 300 — ≦0.01 301 — ≦0.01 302— ≦0.1 303 — ≦0.1 304 — ≦1 305 — ≦0.1 306 — ≦0.1 307 — ≦0.01 308 — ≦0.01309 — ≦0.1 310 — ≦1 311 — ≦0.1 312 — ≦0.1 313 — ≦0.1 314 — ≦1 315 — ≦1316 — ≦1 317 — ≦0.1 318 — ≦0.01 319 — ≦0.1 320 — ≦0.1 321 — ≦0.01 322 —≦0.01 323 — ≦1 324 — ≦0.01 325 — ≦1 326 — ≦1

We claim:
 1. An aminotetraline derivative of the formula (I)

wherein A is a 5- or 6-membered ring; R² is hydrogen, halogen,C₁-C₆-alkyl, halogenated C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, —CN,C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionally substituted C₆-C₁₂-aryl,hydroxy, C₁-C₆-alkoxy, halogenated C₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl,C₂-C₆-alkenyloxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy,C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,aminosulfonyl, amino, C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro oroptionally substituted C₃-C₁₂-heterocyclyl, or two radicals R² togetherwith the ring atoms of A to which they are bound form a 5- or 6 memberedring; R³ is hydrogen, halogen, C₁-C₆-alkyl or C₁-C₆-alkoxy, or tworadicals R³ together with the carbon atom to which they are attachedform a carbonyl group; R^(4a) is hydrogen, C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenated C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl, CH₂CN,—CHO, C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl,C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂, —C(═NH)NHCN,C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO orC₃-C₁₂-heterocyclyl; R^(4b) is hydrogen, C₁-C₆-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,amino-C₁-C₄-alkyl, CH₂CN, —CHO, C₁-C₄-alkylcarbonyl, (halogenatedC₁-C₄-alkyl)carbonyl, C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl,C₆-C₁₂-aryloxycarbonyl, C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl,—C(═NH)NH₂, —C(═NH)NHCN, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl,amino, —NO or C₃-C₁₂-heterocyclyl; or R^(4a), R^(4b) together areoptionally substituted C₁-C₆-alkylene, wherein one —CH₂— ofC₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁶; X² is —O—,—NR⁶—, —S—, >CR^(12a)R^(12b) or a bond; X³ is —O—, —NR⁷—, —S—,>CR^(13a)R^(13b) or a bond; R⁵ is optionally substituted C₆-C₁₂-aryl,optionally substituted C₃-C₁₂-cycloalkyl or optionally substitutedC₃-C₁₂-heterocyclyl; n is 0, 1 or 2; R⁶ is hydrogen or C₁-C₆-alkyl; R⁷is hydrogen or C₁-C₆-alkyl; R^(12a) is hydrogen, optionally substitutedC₁-C₆-alkyl, C₁-C₆-alkylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylamino-C₁-C₄-alkyl, C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl,optionally substituted C₆-C₁₂-aryl or hydroxy; R^(12b) is hydrogen orC₁-C₆-alkyl; or R^(12a), R^(12b) together are carbonyl or optionallysubstituted C₁-C₄-alkylene, wherein one —CH₂— of C₁-C₄-alkylene may bereplaced by an oxygen atom or —NR¹⁴—; R^(13a) is hydrogen, optionallysubstituted C₁-C₆-alkyl, C₁-C₆-alkylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylamino-C₁-C₄-alkyl, C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl,optionally substituted C₆-C₁₂-aryl or hydroxy; R^(13b) is hydrogen orC₁-C₆-alkyl; or R^(13a), R^(13b) together are carbonyl or optionallysubstituted C₁-C₄-alkylene, wherein one —CH₂— of C₁-C₄-alkylene may bereplaced by an oxygen atom or —NR¹⁵—; R¹⁴ is hydrogen or C₁-C₆-alkyl;R¹⁵ is hydrogen or C₁-C₆-alkyl; and R¹⁶ is hydrogen or C₁-C₆-alkyl; or aphysiologically tolerated salt thereof.
 2. The compound as claimed inclaim 1, wherein A is a benzene ring or a ring selected from the groupconsisting of the following 5- or 6-membered heterocyclic rings:


3. The compound as claimed in claim 1, having one of the formulae


4. The compound as claimed in claim 1, wherein R² is hydrogen, halogen,or C₁-C₆-alkoxy.
 5. The compound as claimed in claim 1, having one ofthe formulae


6. The compound as claimed in claim 1, wherein R³ is hydrogen orC₁-C₆-alkyl.
 7. The compound as claimed in claim 1, having the formula

wherein R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(3f) independentlyhave the meaning of R³.
 8. The compound as claimed in claim 1, whereinR^(4a) is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl,halogenated C₁-C₄-alkyl, amino-C₁-C₄-alkyl, CH₂CN, —CHO,C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl,—C(═NH)NH₂, —C(═NH)NHCN, C₁-C₆-alkylsulfonyl, amino, —NO, orC₃-C₁₂-heterocyclyl.
 9. The compound as claimed in claim 1, whereinR^(4b) is hydrogen or C₁-C₆-alkyl.
 10. The compound as claimed in claim1, wherein R^(4a), R^(4b) together are optionally substitutedC₁-C₆-alkylene, wherein one —CH₂— of C₁-C₄-alkylene may be replaced byan oxygen atom.
 11. The compound as claimed in claim 1, wherein X² isCR^(12a)R^(12b).
 12. The compound as claimed in claim 11, wherein X³ isa bond.
 13. The compound as claimed in claim 1, wherein R^(12a) ishydrogen or C₁-C₆-alkyl, and R^(12b) is hydrogen or C₁-C₆-alkyl.
 14. Thecompound as claimed in claim 1, wherein R^(12a), and R^(12b) togetherare optionally substituted C₁-C₄-alkylene.
 15. The compound as claimedin claim 1, wherein R⁵ is optionally substituted aryl or optionallysubstituted C₃-C₁₂-cycloalkyl.
 16. The compound as claimed in claim 15,having the formula

wherein R^(15a), R^(15b), R^(15c), R^(15d), and R^(15e) independentlyare hydrogen, halogen, optionally substituted C₁-C₆-alkyl, halogenatedC₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino, or C₃-C₁₂-heterocyclyl.
 17. The compound as claimedin claim 1, wherein n is
 1. 18. The compound as claimed in claim 1,which is:7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;Ethyl[7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate;or tert-Butyl[7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate;or a physiologically tolerated salt thereof.
 19. A pharmaceuticalcomposition comprising a carrier and a compound of claim
 1. 20. A methodfor treating a neurologic or psychiatric disorder or pain in a mammalianpatient in need thereof which comprises administering to the patient atherapeutically effective amount of a compound of claim 1, wherein theneurologic disorder is selected from the group consisting of dementia,cognitive impairment, and attention deficit disorder, and wherein thepsychiatric disorder is selected from the group consisting of anxietydisorder, depression, bipolar disorder, schizophrenia, and psychosis.